U.S. patent application number 16/080358 was filed with the patent office on 2019-02-14 for process and intermediates for the production of 17(20)-ene b-seco steroids.
This patent application is currently assigned to Patheon Austria GmbH &. The applicant listed for this patent is Patheon Austria GmbH & Co KG. Invention is credited to Denis Viktorovich AREFYEV, Panos KALARITIS, George Petros YIANNIKOUROS.
Application Number | 20190047939 16/080358 |
Document ID | / |
Family ID | 58213075 |
Filed Date | 2019-02-14 |
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United States Patent
Application |
20190047939 |
Kind Code |
A1 |
YIANNIKOUROS; George Petros ;
et al. |
February 14, 2019 |
PROCESS AND INTERMEDIATES FOR THE PRODUCTION OF 17(20)-ENE B-SECO
STEROIDS
Abstract
##STR00001## The invention pertains to a process for producing a
compound of formula (11) wherein R.sup.7 and R.sup.8 are each
independently selected from H, halogen, alkyl, aryl, or alkylaryl,
R.sup.42 is H or a protective group, R.sup.43 is H or R.sup.3,
wherein R.sup.3 is a protective group, by contacting a compound of
formula (10) with an olefmation reagent, wherein compound of
formula (10) comprises a counter acid X.sup.1 when R.sup.42.dbd.H
and R.sup.43.dbd.H.
Inventors: |
YIANNIKOUROS; George Petros;
(Florence, SC) ; KALARITIS; Panos; (Florence,
SC) ; AREFYEV; Denis Viktorovich; (Florence,
SC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Patheon Austria GmbH & Co KG |
Linz |
|
AT |
|
|
Assignee: |
; Patheon Austria GmbH
&
Linz
AU
|
Family ID: |
58213075 |
Appl. No.: |
16/080358 |
Filed: |
March 1, 2017 |
PCT Filed: |
March 1, 2017 |
PCT NO: |
PCT/EP2017/054838 |
371 Date: |
August 28, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62302410 |
Mar 2, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07J 1/0011 20130101;
C07C 41/01 20130101; C07C 249/02 20130101; C07C 2602/24 20170501;
C07C 2601/14 20170501; C07C 213/08 20130101; C07J 21/008 20130101;
Y02P 20/55 20151101; C07C 62/26 20130101; C07C 217/52 20130101;
Y02P 20/582 20151101; A61P 29/00 20180101; C07F 7/1804 20130101;
A61P 13/10 20180101; C07J 51/00 20130101; C07C 251/06 20130101;
C07C 45/29 20130101 |
International
Class: |
C07C 213/08 20060101
C07C213/08; C07C 45/29 20060101 C07C045/29; C07C 41/01 20060101
C07C041/01; C07C 249/02 20060101 C07C249/02; C07J 21/00 20060101
C07J021/00; C07C 62/26 20060101 C07C062/26; C07C 251/06 20060101
C07C251/06; C07C 217/52 20060101 C07C217/52 |
Claims
1. A process for producing a compound of formula (11) ##STR00079##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, aryl, or alkylaryl, R.sup.42 is H or a protective
group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective
group, by contacting a compound of formula (10) ##STR00080## with
an olefination reagent, wherein compound of formula (10) comprises
a counter acid X.sup.1 when R.sup.42.dbd.H and R.sup.43.dbd.H.
2. Process according to claim further comprising a step of
contacting a compound of formula (3) ##STR00081## wherein R.sup.1,
R.sup.2 and R.sup.3 are protective groups, with a second oxidizing
agent to obtain a compound of formula (4) ##STR00082##
3. Process according to claim 2, further comprising the step of
contacting a compound of formula (9). ##STR00083## wherein R.sup.1,
R.sup.2 and R.sup.3 are protective groups, with an first acid
capable of forming a pharmaceutically acceptable salt to obtain the
compound of formula (10).
4. Process according to claim 2, further comprising: a) converting
the compound of formula (4) to a compound of formula (7)
##STR00084## comprising the steps selected from: iv) contacting the
compound of formula (4) with a first base and a third protective
reagent to form a compound of formula (5) ##STR00085## wherein
R.sup.4 is a protective group, and contacting the compound of
formula (5) with a third oxidizing agent and optionally with a
fourth protective reagent to obtain a compound of formula (6)
##STR00086## wherein R.sup.5 is H or a protective group; and
contacting the compound of formula (6) with a fourth oxidizing
agent to obtain the compound of formula (7); or v) contacting the
compound of formula (4) with a first base and a third oxidizing
agent and optionally with a fourth protective reagent to obtain a
compound of formula (6), wherein the molar ratio of the third
oxidizing agent and the compound of formula (4) is at most 1.5; and
contacting a compound of formula (6) with a fourth oxidizing agent
to obtain the compound of formula (7); or vi) contacting the
compound of formula (4) with a first base and a third oxidizing
agent and optionally with a fourth protective reagent to obtain the
compound of formula (7), wherein the molar ratio of the third
oxidizing agent and the compound of formula (4) is at least 1.5;
wherein the process further comprises the steps of: b) contacting
the compound of formula (7) with a compound of formula (7a)
NH.sub.2--R.sup.6 (7a) wherein R.sup.6 is either H or --OR.sup.22,
wherein R.sup.22 is either H or a protective group, to obtain a
compound of formula (8) ##STR00087## and c) contacting the compound
of formula (8) with a reducing agent to obtain the compound of
formula (9).
5. A process for preparing a compound of formula (12) ##STR00088##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, cycloalkyl, alkoxy, aryloxy, aryl, or alkylaryl and
X is a counter acid, comprising the steps of claim 1, further
comprising the conversion of the compound of formula (11) with a
second acid capable of forming a pharmaceutically acceptable salt
to obtain the compound of formula (12).
6. A process for preparing a compound of formula (4) ##STR00089##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups,
comprising the step of contacting a compound of formula (3)
##STR00090## with a second oxidizing agent to obtain the compound
of formula (4).
7. (canceled)
8. A compound of formula (5) ##STR00091## wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are protective groups.
9. A compound of formula (6) ##STR00092## wherein R.sup.1, R.sup.2
and R.sup.3 are protective groups, and R.sup.5 is H or a protective
group.
10. A compound of formula (7) ##STR00093## wherein R.sup.1, R.sup.2
and R.sup.3 are protective groups.
11. A compound of formula (8) ##STR00094## wherein R.sup.1, R.sup.2
and R.sup.3 are protective groups and R.sup.6 is either H or
--OR.sup.22, wherein R.sup.22 is either H or a protective
group.
12. A compound of formula (9) ##STR00095## wherein R.sup.1, R.sup.2
and R.sup.3 are protective groups.
13. (canceled)
14. (canceled)
15. (canceled)
Description
[0001] The present invention relates to a process for the
production of secosteroids, in particular octahydro-1H-indene
derivatives and further pertains to novel intermediates prepared in
the process of the invention and to the use of the compounds
produced with the process of the invention in a process for the
preparation of an active pharmaceutical ingredient, for example an
active pharmaceutical ingredient useful for the treatment of
inflammatory diseases, bladder pain syndrome/interstitial cystitis
and related disorders.
BACKGROUND OF THE INVENTION
[0002] Secosteroids, in particular octahydro-1H-indene derivatives,
more in particular 5-cyclohexyloctahydro-1H-indene derivatives are
well known as anti-inflammatory agents (WO 2004092100) and for the
treatment of disorders or conditions that would benefit from SHIP1
(SH2 domain-containing inositol phosphatase) modulation, e.g.
immune and hemopoietic disorders (WO 2014143561). A target compound
which is of particular interest in this respect is
(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)
-7a-methyl-1-methyleneoctahydro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methyl-
cyclohexan-1-ol acetate.
[0003] Known synthetic methods for the preparation of
5-cyclohexyloctahydro-1H-indene derivatives which can act as SHIP1
modulators can be performed starting from a number of steroid
percursors including 4-androsten-3,17-dione and others with C3
oxygen functionalities and .DELTA..sup.5 carbon-carbon double bonds
such as dehydroisoandrosterone as described in U.S. Pat. Nos.
6,046,185, 7,601,874 and WO 2014/143561.
[0004] The disadvantage of the known synthetic methods is the
process complexity, i.e. considerably more than 10 steps are needed
to obtain the desired secosteroids when starting from the
aforementioned steroid precursors to obtain the desired
secosteroids, and several chromatographic purification steps are
required. The overall yields of the known processes are generally
low.
[0005] The object of the present invention is to provide an
alternative process.
SUMMARY OF THE INVENTION
[0006] The object of the invention is achieved by a process for
producing a compound of formula (11)
##STR00002##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, aryl, or arylalkyl, R.sup.42 is H or a protective
group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective
group, by contacting a compound of formula (10)
##STR00003##
with an olefination reagent, wherein compound of formula (10)
comprises a counter acid X.sup.1 when R.sup.42.dbd.H and
R.sup.43.dbd.H. The process of the invention enables an alternative
process for the production of the compound of formula (11). The
alternative process generally allows for less process steps
compared to conventional processes. The process is generally less
time-consuming, less complex, more cost efficient and increases
flexibility. A further advantage of this process is that the
compound of formula (11) can be isolated as a solid. One embodiment
of the process of the present invention may be exemplified by the
following scheme:
##STR00004## ##STR00005## ##STR00006##
[0007] Some of the conversion steps, in particular steps A and B, C
and D, E to G, and H to J, can be performed without intermediate
isolation. This generally renders the process of the invention to
be less time-consuming, less complex and more cost efficient. U.S.
Pat. No. 6,046,185 and WO 2004/092100 when combined disclose a
synthetic pathway to produce a compound of formula (12) from
dehydroepiandrosteron (DHEA). This pathway generally requires
considerably more steps than the process of the invention.
Typically overall yields of the present invention are similar or
higher than the yield from conventional synthetic pathways. The
process of the invention allows for considerably less purification
steps using chromatography compared to conventional processes. Such
purification steps are laborious and generally render the process
not to be time and/or cost efficient. The process of the invention
enables a process absent of such chromatographic purification
steps. Chromatographic purifications usually have disadvantages in
that a significant amount of eluents is necessary for their
operation and that they may limit the throughput of a process.
Moreover the reprocessing of the mobile phase may be
energy-intensive and the stationary phase may cause significant
amounts of waste. In general the "Material input per unit of
service" (MIPS) value of chromatographic purification to reach a
desired product quality is significant. With the process of the
invention the compound of formula (12) can easily be obtained at a
purity level which is generally higher compared to conventional
processes. A further advantage of the process of the present
invention is that all intermediates may be readily isolated as
solids, which generally allows for a good storage stability as well
as easy transport enabling the performance of the process at two or
more production facilities at different locations.
[0008] Compound of formula (11) may be further contacted with a
second acid which forms a non-toxic salt to obtain a compound of
formula (12)
##STR00007##
[0009] The present invention allows an alternative process to
obtain the compound of formula (12) with fewer steps than known
from conventional processes.
[0010] R.sup.7 and R.sup.8 are each independently selected as
described above. Preferably R.sup.7 and R.sup.8 are independently
hydrogen, halogen, linear or branched C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.8 alkoxy, C.sub.6-C.sub.10 aryloxy, C.sub.3-C.sub.10
cycloalkyl, C.sub.5-C.sub.10 aryl or C.sub.7-C.sub.10 arylalkyl.
More preferably R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, fluorine, chlorine, methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,
methoxy, ethoxy, propoxy, butoxy, phenoxy, benzoxy, cyclopropyl,
cyclobutyl, cycloheptyl, phenyl, naphthyl, tosyl, and benzyl. Even
more preferably R.sup.7 and R.sup.8 are independently selected from
the group consisting of hydrogen, fluorine, chlorine and methyl.
Most preferably R.sup.7 and R.sup.8 are hydrogen.
[0011] X is an acid capable of forming a pharmaceutically
acceptable salt with the compound of formula (11) to obtain
compound of formula (12). Such acids can be any suitable acid known
in the art. Examples of such acids are described in P. H. Stahl and
C. G. Wermuth, editors, Handbook of Pharmaceutical Salts:
Properties, Selection and Use, Weinheim/Zurich:Wiley-VCH/VHCA,
2011. Preferably, X is selected from the group consisting of any
mineral acid and any organic mono- or di-acid. More preferably, X
is selected from the group consisting of hydrochloric acid,
hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid,
acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic
acid, maleic acid, malonic acid, succinic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic
acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic
acid and salicylic acid. Even more preferably X is selected from
the group consisting of acetic acid, hydrochloric acid, hydrobromic
acid, sulphuric acid, phosphoric acid, oxalic acid and tartaric
acid. Even more preferably X is selected from the group consisting
of acetic acid, oxalic acid and tartaric acid. Most preferably X is
acetic acid.
The term second acid is equivalent to X and selected
accordingly.
[0012] "Pharmaceutically acceptable salt" in the context of the
present invention refers to acid addition salts.
[0013] Acid addition salts refer to those salts formed from
compounds of the present invention and inorganic acids such as
hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid,
phosphoric acid and the like, and/or organic acids such as acetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid and the like.
[0014] With the term "independently" is meant that each of the
substituents may be chosen individually. That is, e.g. R.sup.7 and
R.sup.8 can be different or the same; this means that in case of
more than two substituents also one can be different from the
others.
The substituents R.sup.1 to R.sup.43 of the present invention may
be branched and/or substituted. Preferably R.sup.1 to R.sup.43 are
unbranched. More preferably R.sup.1 to R.sup.43 are unbranched and
unsubstituted.
[0015] The whole process or at least parts (e.g. single steps or
even parts of single steps) of the process can either be performed
in batch, semi-continuous or continuous production mode.
[0016] R.sup.3 may be any protective group for hydroxyl groups
known in the art. Examples of suitable protective groups for
hydroxyl groups are described in T. W. Greene, P. G. M. Wutts
"Protective Groups in Organic Synthesis", John Wiley & Sons,
5.sup.th Ed., 2014, pages 17-374. Preferably, R.sup.3 is a linear
or branched alkyl or alkenyl group having 1 to 8 carbon atoms,
silyl, silane, siloxane, alkoxyalkyl, aryloxyalkyl, acyl, benzoyl,
benzyl, methylthiomethyl, pivaloyl, pyranyl, or triarylalkyl. More
preferably R.sup.3 is selected from the group consisting of methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,
trimethylsilyl (TMS), triethylsilyl (TES), tert.-butyldimethylsilyl
(TBS/TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl
(TIPS), silane, tri-iso-propylsilyloxymethyl (TOM), methoxymethyl
(MOM), ethoxyethyl (EE), benzyloxymethyl (BOM), 4-methoxybenzyl
(PMB), acyl, benzoyl, benzyl, methylthiomethyl (MTM), pivaloyl,
2-tetrahydropyranyl (THP) and triphenylmethyl (Tr). More preferably
R.sup.3 is selected from the group consisting of trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), silane,
and tri-iso-propylsilyloxymethyl (TOM). Even more preferably
R.sup.3 is selected from the group consisting of trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS). Most
preferably R.sup.3 is tert.-butyldimethylsilyl (TBS/TBDMS).
[0017] R.sup.42 may be any protective group known in the art, in
particular suitable to protect amino groups. Examples of suitable
protective groups for amino groups are described in T. W. Greene,
P. G. M. Wutts "Protective Groups in Organic Synthesis", John Wiley
& Sons, 5.sup.th Ed., 2014, pages 895-1115. Preferably,
R.sup.42 is a protective group for amino groups capable of forming
a carbamate, an amide, a N-alkyl or N-aryl amine, or a N-hetero
atom derivative with the compounds of the present invention. More
preferably R.sup.42 is selected from the group consisting of
alkoxycarbonyl, arylalkoxycarbonyl, formyl, acetyl, alkyl, aryl,
arylalkyl and alkenyl. Even more preferably R.sup.42 is selected
from the group consisting of methyl oxycarbonyl, ethyl oxycarbonyl,
9-flourenylmethyl oxycarbonyl,
1,1-dioxobenzo[b]thiophene-2-ylmethyl oxycarbonyl,
2-trimethylsilylethyl oxycarbonyl, 2-phenylethyl oxycarbonyl,
1-(1-adamantyl)-1-methylethyl oxycarbonyl,
(2-pivaloylamino)-1,1-dimethylethyl oxycarbonyl, tert-butyl
oxycarbonyl, 1-adamantyl oxycarbonyl, 2-adamantyl oxycarbonyl,
1-isopropylallyl oxycarbonyl, benzyl oxycarbonyl, formyl, acetyl,
trifluoroacetyl, trichloroacetyl, phenylacetyl, benzyl,
triphenylmethyl, p-tosyl, t-butyl, allyl and diphenylmethyl. Even
more preferably R.sup.42 is selected from the group consisting of
9-flourenylmethyl oxycarbonyl, tert-butyl oxycarbonyl, formyl,
acetyl, trifluoroacetyl, benzyl, triphenylmethyl and p-tosyl. Most
preferably, R.sup.42 is tert-butyl oxycarbonyl.
[0018] "Heteroatom" may be a halogen, nitrogen, oxygen,
phosphorous, silicon, boron or sulphur atom. Groups containing more
than one heteroatom may contain different heteroatoms
[0019] X.sup.1 represents a counter acid which together with the
compounds of the present invention, in particular with compound of
formula (9) may form a pharmaceutically acceptable salt to obtain
compound of formula (10) and which generally may be selected as
known in the art. Examples for the selection of X.sup.1 are
provided by P. H. Stahl and C. G. Wermuth, editors, Handbook of
Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich:Wiley-VCHNHCA, 2011. Preferably, X.sup.1 is
selected from the group consisting of any mineral acid and any
organic mono- or di-acid. More preferably, X.sup.1 is selected from
the group consisting of hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid, acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic
acid, malonic acid, succinic acid, fumaric acid, tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid
and salicylic acid. Even more preferably X.sup.1 is selected from
the group consisting of acetic acid, benzenesulfonic acid,
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid, oxalic acid, tartaric acid and p-toluenesulfonic acid. Even
more preferably X.sup.1 is selected from the group consisting of
benzenesulfonic acid and p-toluenesulfonic acid. Most preferably
X.sup.1 is p-toluenesulfonic acid.
[0020] The olefination reagent can be any suitable olefination
reagent known in the art. The olefination reagent is generally a
compound which is able to transform the keto group of compound of
formula (10) into an alkene as present in compound of formula (11).
Preferably, the olefination reagent is selected from the group
consisting of a triphenylphosphonium ylide, a .alpha.-silyl
carbanion, a stabilized phosphonate carbanion, an aryl sulfone, a
sulfoxide, a Tebbe reagent, a Lombardo reagent and a Petasis
reagent. More preferably, the olefination reagent is selected from
the group consisting of a triphenylphosphonium methylide,
.alpha.-trimethylsilyl acetate, .alpha.-trimethylsilyl
aminoacetonitrile, methyldiethylphosphonoacetate,
isopropyldiethylphosphoneacetate,
tert.-butyldiethyl-phosphonoacetate, methyl phenyl sulfone, ethyl
phenyl sulfone, benzothiazole methyl sulfone (BT-sulfone),
1-phenyl-1H-tetrazole methyl sulfone (PT-sulfone), a Tebbe reagent,
a Lombardo reagent and a Petasis reagent. Even more preferably the
olefination reagent is selected from the group consisting of
triphenylphosphonium methylide, a Tebbe reagent, a Lombardo reagent
and a Petasis reagent. Most preferably the olefination reagent is
triphenylphosphonium methylide.
[0021] The triphenylphosphonium ylide may be generated in situ from
methyltriphenylphosphonium bromide (Ph.sub.3PMeBr) and potassium
tert-butoxide (KOt-Bu).
[0022] In case the olefination reagent is a triphenylphosphonium
ylide, a third base may be present to obtain the ylide from a
phosphonium precursor which third base may be selected from organic
or inorganic bases. Preferably, such third base is selected from
the group consisting of potassium tert.-butoxide (KOt-Bu),
potassium hydride with paraffin (KH(P)), sodium hydride (NaH),
sodium hexamethyl disilylamide (NaHMDS), pyridine, triethylamine
(NEt.sub.3) lithiumdiisopropylamide (LDA) and sodium methoxide
(NaOMe). More preferably such third base is selected from the group
consisting of potassium tert.-butoxide (KOt-Bu), sodium hexamethyl
disilylamide (NaHMDS), pyridine, triethylamine (NEt.sub.3)
lithiumdiisopropylamide (LDA) and sodium methoxide (NaOMe). Most
preferably, such third base is potassium tert.-butoxide
(KOt-Bu).
[0023] In case the olefination reagent is a .alpha.-silyl
carbanion, an acid or a fourth base may be present in order to
modify the stereoselectivity of the reaction. In case an acid is
present, preferably the acid is selected from the group consisting
of acetic acid (AcOH), sulphuric acid (H.sub.2SO.sub.4) and
BF.sub.3.OEt.sub.2. More preferably the acid is selected from the
group consisting of acetic acid and sulphuric acid. Most preferably
the acid is sulphuric acid. In case a fourth base is present,
preferably the fourth base is selected from the group consisting of
sodium hydride (NaH), potassium hydride (KH) and potassium
tert.-butoxide (KOt-Bu). More preferably the fourth base is
selected from the group consisting of potassium hydride (KH) and
potassium tert.-butoxide (KOt-Bu). Most preferably the fourth base
is potassium tert.-butoxide (KOt-Bu).
[0024] In case the olefination reagent is an aryl sulfone, a metal
containing fifth base may be present. Preferably such fifth base is
a strong metal containing base. More preferably such fifth base is
selected from the group consisting of sodium methoxide (NaOMe),
sodium bis(trimethylsilyl)amide (NaHMDS) and lithium
bis(trimethylsilyl) amide (LiHMDS). Most preferably such fifth base
is sodium methoxide (NaOMe).
[0025] In case the olefination reagent is an aryl sulfone, the
initially formed beta-oxido sulfone may be reduced by a second
reducing agent. Such second reducing agent preferably is selected
from the group consisting of Sml.sub.2, Bu.sub.3SnH, Li or Na in
ammonia, Na.sub.2S.sub.2O4, Raney/Ni, Al(Hg) amalgam and
LiAlH.sub.4. More preferably such second reducing agent is selected
from the group consisting of Sml.sub.2, Li or Na in ammonia and
Al(Hg) amalgam. Most preferably such second reducing agent is
Sml.sub.2.
[0026] Contacting a compound of formula (10) with an olefination
reagent to obtain a compound of formula (11) may be performed in
the presence of a solvent or mixture of solvents. Suitable solvents
include water, organic solvents or mixtures of organic solvents or
mixtures thereof. Preferably the solvent is selected from the group
consisting of water, methanol, tetrahydrofuran (THF), toluene,
xylene and benzene or mixtures thereof. More preferably the solvent
is selected from the group consisting of methanol and
tetrahydrofuran (THF) or mixtures thereof. Most preferably the
solvent is tetrahydrofuran (THF).
[0027] Generally, the reaction temperature for producing a compound
of formula (11) by contacting a compound of formula (10) with an
olefination reagent ranges from -90.degree. C. up to reflux of the
solvent or solvent mixture. Preferably, the temperature is at least
-80.degree. C., more preferably at least -60.degree. C., even more
preferably at least -50.degree. C., even more preferably at least
-30.degree. C., even more preferably at least -15.degree. C., even
more preferably at least -5.degree. C., most preferably at least
0.degree. C. Preferably, the temperature is at most 70.degree. C.,
more preferably at most 60.degree. C., even more preferably at most
45.degree. C., and most preferably at most 30.degree. C.
[0028] In one aspect of the invention the process further comprises
a step of contacting a compound of formula (3)
##STR00008##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
second oxidizing agent to obtain a compound of formula (4)
##STR00009##
[0029] This step allows for the production of the compounds of
formula (10) and formula (11) via various routes. This step renders
any process for producing the compound of formula (11) to be
distinctively different from the existing processes of the prior
art, in particular to U.S. Pat. No. 6,046,185 and WO 2004/09210. A
further advantage is that the compound of formula (4) can be
isolated as a solid, which allows for an increased flexibility of
the process, e.g. further processing at a different location.
R.sup.3 is a protective group as previously disclosed.
[0030] R.sup.1 and R.sup.2 are protective groups. Such protective
groups are independently chosen and/or together form a cyclic
protective group. Such protective groups may be any protective
group known in the art, in particular suitable to protect hydroxyl
groups. Examples of suitable protective groups for hydroxyl groups
are described in T. W. Greene, P. G. M. Wutts "Protective Groups in
Organic Synthesis", John Wiley & Sons, 5.sup.th Ed., 2014,
pages 17-374. Preferably, R.sup.1 and R.sup.2 independently are
linear or branched alkyl or alkenyl groups having 1 to 8 carbon
atoms, silyl, silane, siloxane, alkoxyalkyl, aryloxyalkyl, acyl,
benzoyl, benzyl, methylthiomethyl, pivaloyl, pyranyl, triarylalkyl,
or together form a hydrocarbon group having the formula
##STR00010##
wherein a is 0 or 1 and R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13 and R.sup.14 are independently hydrogen, alkynyl or
linear, branched, or cyclic alkyl or alkenyl groups having 1 to 18
carbon atoms, or an aryl or alkylaryl group, wherein the alkyl,
alkenyl, aryl, or alkylaryl groups include one or more additional
functional groups such as halogen, tertiary amine, carbonate,
ether, ester, carbonyl, urethane, imide, amide, sulfone,
sulphonamide, mercapto, disulphide, phosphate, phosphonoxy, silane,
or siliyl. More preferably R.sup.1 and R.sup.2 are independently
selected from the group consisting of methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, tert-butyl, trimethylsilyl (TMS),
triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), silane,
tri-iso-propylsilyloxymethyl (TOM), methoxymethyl (MOM),
ethoxyethyl (EE), benzyloxymethyl (BOM), 4-methoxybenzyl (PMB),
acyl, benzoyl, benzyl, methylthiomethyl (MTM), pivaloyl,
2-tetrahydropyranyl (THP) and triphenylmethyl (Tr), or together
form a hydrocarbon group having the formula
##STR00011##
wherein a is 0 or 1 and R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13 and R.sup.14 are independently hydrogen, ethinyl,
1-propinyl, 3-propinyl, 1-butin-1-yl, 2-butin-1-yl, 3-butin-1-yl,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, pentane, isopentane, neopentane, cyclopropane,
cyclobutane, cyclopentane, cyclohexane, vinyl, allyl, crotyl,
cyclopentadienyl, phenyl or benzyl. Even more preferably R.sup.1
and R.sup.2 form a hydrocarbon group having the formula
##STR00012##
wherein a is 0 or 1 and R.sup.9, R.sup.10, R.sup.11, R.sup.12,
R.sup.13 and R.sup.14 are independently hydrogen, ethinyl,
1-propinyl, 3-propinyl, 1-butin-1-yl, 2-butin-1-yl, 3-butin-1-yl,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, pentane, isopentane, neopentane, cyclopropane,
cyclobutane, cyclopentane, cyclohexane, vinyl, allyl, crotyl,
cyclopentadienyl, phenyl or benzyl. Even more preferably R.sup.1
and R.sup.eform a hydrocarbon group having the formula
##STR00013##
wherein a is 0 and R.sup.9, R.sup.10, R.sup.13 and R.sup.14 are
independently hydrogen, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, tert-butyl. Most preferably R.sup.1 and R.sup.2
form a hydrocarbon group having the formula
##STR00014##
wherein a is 0 and R.sup.9, R.sup.10, R.sup.13 and R.sup.14 are
independently hydrogen.
[0031] The second oxidizing agent is a member of the group of
compounds which is able to transform a hydroxyl group into a keto
group, in particular in compound of formula (3) of the invention.
Preferably the second oxidizing agent of the invention is selected
from the group consisting of dichromate, chromium trioxide
(CrO.sub.3), chromium trioxide derivatives, hypervalent iodines,
oxalyl chloride, trifluoroacetic anhydride, metal alkoxides,
silver(I) carbonate, activated dimethyl sulfoxide (DMSO) and
tetrapropylammoniumperruthenat (TPAP). More preferably the second
oxidizing agent of the invention is selected from the group
consisting of potassium dichromate, pyridinium dichromate (PDC),
chromium trioxide (CrO.sub.3), CrO.sub.3-amine reagents,
2-iodoxybenzoic acid, Dess-Martin periodinane (DMP), oxalyl
chloride, trifluoroacetic anhydride, activated dimethyl sulfoxide
(DMSO), aluminium isopropoxide (Al(i-PrO).sub.3), potassium
tert-butoxide (KOt-Bu), silver(I) carbonate and
tetrapropylammoniumperruthenat (TRAP). Even more preferably the
second oxidizing agent of the invention is selected from the group
consisting of potassium dichromate, pyridinium dichromate (PDC),
chromium trioxide (CrO.sub.3), pyridinium chlorochromate,
2-iodoxybenzoic acid, Dess-Martin periodinane (DMP) and activated
dimethyl sulfoxide (DMSO). Even more preferably the second
oxidizing agent of the present invention is selected from the group
consisting of 2-iodobenzoic acid and Dess-Martin periodinane (DMP).
Most preferably the second oxidizing agent of the present invention
is 2-iodobenzoic acid.
[0032] Suitable means to activate dimethyl sulfoxide include the
sulfur trioxide pyridine complex (pyridine-50.sub.3 complex) in the
presence of trimethylamine (TEA), N-chlorosuccinimide (NCS) and
dimethylsulfide (DMS) in the presence of trimethylamine (TEA) or
dicyclohexyl carbodiimide (DCC) and catalytic amounts of
(moderately acidic) acid (e.g. anhydrous phosphoric acid
(H.sub.3PO.sub.4) or dichloroacetic acid (Cl.sub.2CCO.sub.2H) or
pyridiniumsalts of strong acids (e.g pyr-HCl, pyr-TFA).
[0033] The transformation of compound of formula (3) with a second
oxidizing agent to obtain a compound of formula (4) may be
performed in the presence of a solvent or a mixture of solvents.
Suitable solvents include ethyl acetate (EtOAc), dimethyl sulfoxide
(DMSO), dichloromethane (DCM), acetone, toluene, benzene,
acetonitrile (MeCN), ionic liquids or tetrahydrofuran (THF).
Preferably the solvent is selected from the group consisting of
ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), dichloromethane
(DCM) and toluene or mixtures thereof. Even more preferably the
solvent is selected from the group consisting of ethyl acetate
(EtOAc) and dimethyl sulfoxide (DMSO) or mixtures thereof. Even
more preferably the solvent is a mixture of ethyl acetate (EtOAc)
and dimethyl sulfoxide (DMSO). Most preferably the solvent is
dimethyl sulfoxide (DMSO).
[0034] Generally, the reaction temperature for producing a compound
of formula (4) by contacting a compound of formula (3) with a
second oxidizing agent ranges from -20.degree. C. up to reflux of
the solvent or solvent mixture. Preferably, the reaction
temperature is at least -10.degree. C., more preferably at least
0.degree. C., even more preferably at least 10.degree. C. and most
preferably at least 20.degree. C. Preferably, the reaction
temperature is at most 70.degree. C., more preferably at most
60.degree. C., even more preferably at most 45.degree. C. and most
preferably at most 30.degree. C.
[0035] The invention further pertains to a process for preparing a
compound of formula (4)
##STR00015##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups,
comprising the step of contacting a compound of formula (3)
##STR00016##
with a second oxidizing agent to obtain the compound of formula
(4). R.sup.1, R.sup.2 and R.sup.3 are selected as described
above.
[0036] The invention further pertains to the compound of formula
(4)
##STR00017##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups.
[0037] In another aspect of the invention the process further
comprises [0038] a) converting the compound of formula (4) to a
compound of formula (7)
[0038] ##STR00018## [0039] comprising the steps selected from:
[0040] i) contacting the compound of formula (4) with a second base
and a third protective reagent to form a compound of formula
(5)
[0040] ##STR00019## [0041] wherein R.sup.4 is a protective group,
and [0042] contacting the compound of formula (5) with a third
oxidizing agent and optionally with a fourth protective reagent to
obtain a compound of formula (6)
[0042] ##STR00020## [0043] wherein R.sup.5 is H or a protective
group; and [0044] contacting the compound of formula (6) with a
fourth oxidizing agent to obtain the compound of formula (7); or
[0045] ii) contacting the compound of formula (4) with a second
base and a third oxidizing agent and optionally with a fourth
protective reagent to obtain a compound of formula (6), wherein the
molar ratio of the third oxidizing agent and the compound of
formula (4) is at most 1.5; and contacting a compound of formula
(6) with a fourth oxidizing agent to obtain the compound of formula
(7); or [0046] iii) contacting the compound of formula (4) with a
second base and a third oxidizing agent and optionally with a
fourth protective reagent to obtain the compound of formula (7),
wherein the molar ratio of the third oxidizing agent and the
compound of formula (4) is at least 1.5;
[0047] wherein the process further comprises the steps of: [0048]
a) contacting the compound of formula (7) with a compound of
formula (7a)
[0048] NH.sub.2--R.sup.6 (7a)
[0049] wherein R.sup.6 is either H or --OR.sup.22, wherein R.sup.22
is either H or a protective group, to obtain a compound of formula
(8)
##STR00021##
[0050] and [0051] b) contacting the compound of formula (8) with a
reducing agent to obtain the compound of formula (9).
[0052] Steps i), ii), iii) are alternative processes to convert
compound of formula (4) to compound of formula (7). The compounds
of formula (4), (5), (6), (7), (8) and (9) are novel.
[0053] The compounds of formula (4), (5), (6), (7), (8) and (9) may
provide novel intermediates in the process of the invention. The
compounds of formula (4), (5), (6), (7), (8) and (9) may be
isolated as solids.
R.sup.1, R.sup.2 and R.sup.3 are protective groups as described
above.
[0054] R.sup.4 may be any protective group known in the art, in
particular suitable to protect hydroxyl groups. Examples of
suitable protective groups for hydroxyl groups are described in T.
W. Greene, P. G. M. Wutts "Protective Groups in Organic Synthesis",
John Wiley & Sons, 5.sup.th Ed., 2014, pages 17-374. Preferably
R.sup.4 is a linear or branched alkyl or alkenyl group having 1 to
8 carbon atoms, silyl, silane, siloxane, alkoxyalkyl, aryloxyalkyl,
acyl, benzoyl, benzyl, methylthiomethyl, pivaloyl, pyranyl, or
triarylalkyl. More preferably R.sup.4 is selected from the group
consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, tert-butyl, trimethylsilyl (TMS), triethylsilyl (TES),
tert.-butyldimethylsilyl (TBS/TBDMS), tert-butyldiphenylsilyl
(TBDPS), triisopropylsilyl (TIPS), silane,
tri-iso-propylsilyloxymethyl (TOM), methoxymethyl (MOM),
ethoxyethyl (EE), benzyloxymethyl (BOM), 4-methoxybenzyl (PMB),
acyl, benzoyl, benzyl, methylthiomethyl (MTM), pivaloyl,
2-tetrahydropyranyl (THP) and triphenylmethyl (Tr). More preferably
R.sup.4 is selected from the group consisting of trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), silane
and tri-iso-propylsilyloxymethyl (TOM). Even more preferably
R.sup.4 is selected from the group consisting of trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS). Most
preferably R.sup.4 is tert.-butyldimethylsilyl(TBS/TBDMS).
[0055] Optionally the hydroxyl group in alpha position to the keto
group in compound of formula (6) may be protected by a protecting
group for hydroxyl groups.
[0056] R.sup.5 may be H or any protective group known in the art,
in particular suitable to protect hydroxyl groups. Examples of
suitable protective groups for hydroxyl groups are described in T.
W. Greene, P. G. M. Wutts "Protective Groups in Organic Synthesis",
John Wiley & Sons, 5.sup.th Ed., 2014, pages 17-374. Preferably
R.sup.5 is H, a linear or branched alkyl or alkenyl group having 1
to 8 carbon atoms, silyl, silane, siloxane, alkoxyalkyl,
aryloxyalkyl, acyl, benzoyl, benzyl, methylthiomethyl, pivaloyl,
pyranyl, or triarylalkyl. More preferably R.sup.5 is selected from
the group consisting of H, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, tert-butyl, trimethylsilyl (TMS), triethylsilyl
(TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), silane,
tri-iso-propylsilyloxymethyl (TOM), methoxymethyl (MOM),
ethoxyethyl (EE), benzyloxymethyl (BOM), 4-methoxybenzyl (PMB),
acyl, benzoyl, benzyl, methylthiomethyl (MTM), pivaloyl,
2-tetrahydropyranyl (THP) and triphenylmethyl (Tr). More preferably
R.sup.5 is selected from the group consisting of H, trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), silane,
and tri-iso-propylsilyloxymethyl (TOM). Even more preferably
R.sup.5 is selected from the group consisting of H, trimethylsilyl
(TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBS/TBDMS),
tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS). Most
preferably R.sup.5 is H.
[0057] The process further comprises contacting a compound of
formula (7) with a compound of formula (7a) to obtain a compound of
formula (8).
[0058] Compound of formula (7a) is a member of the group of
compounds which is able to transform the aldehyde moiety of
compound of formula (7) into an imine or more specifically into an
oxime as present in compound of formula (8).
Preferably R.sup.6 is --OR.sup.22.
[0059] R.sup.22 may be H or any protective group known in the art,
in particular suitable to protect hydroxyl groups. Examples of
suitable protective groups for R.sup.22 are described in T. W.
Greene, P. G. M. Wutts "Protective Groups in Organic Synthesis",
John Wiley & Sons, 5th Ed., 2014, pages 17-374. Preferably
R.sup.22 is selected from the group consisting of H, a linear or
branched alkyl or alkenyl group having 1 to 8 carbon atoms, silyl,
silane, siloxane, alkoxyalkyl, aryloxyalkyl, acyl, benzoyl, benzyl,
methylthiomethyl, pivaloyl, pyranyl, and triarylalkyl. More
preferably R.sup.22 is selected from the group consisting of H,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
tert-butyl, trimethylsilyl (TMS), triethylsilyl (TES),
tert.-butyldimethylsilyl (TBS/TBDMS), tert-butyldiphenylsilyl
(TBDPS), triisopropylsilyl (TIPS), silane,
tri-iso-propylsilyloxymethyl (TOM), methoxymethyl (MOM),
ethoxyethyl (EE), benzyloxymethyl (BOM), 4-methoxybenzyl (PMB),
acyl, benzoyl, benzyl, methylthiomethyl (MTM), pivaloyl,
2-tetrahydropyranyl (THP) and triphenylmethyl (Tr). Even more
preferably R.sup.22 is selected from the group consisting of H,
trimethylsilyl (TMS), triethylsilyl (TES), tert.-butyldimethylsilyl
(TBS/TBDMS), tert-butyldiphenylsilyl (TBDPS), triisopropylsilyl
(TIPS), silane and tri-iso-propylsilyloxymethyl (TOM). Even more
preferably R.sup.22 is selected from the group consisting of
trimethylsilyl (TMS), triethylsilyl (TES), tert.-butyldimethylsilyl
(TBS/TBDMS), tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl
(TIPS). Most preferably R.sup.22 is H.
[0060] Compound of formula (7a) is preferably selected from the
group consisting of ammonia (NH.sub.3), hydroxylamine, derivatives
of hydroxylamine (e.g. hydroxylamine-O-sulfonic acid
(H.sub.2NOSO.sub.3H), HON(SO.sub.3Na).sub.2, NH.sub.2OH.HCl,
alkoxyamine or aralkyoxyamine. More preferably compound of formula
(7a) is selected from the group consisting of ammonia (NH.sub.3),
hydroxylamine, hydroxylamine-O-sulfonic acid, NH.sub.2OH.HCl,
linear or branched C.sub.1-C.sub.6 alkoxylamine or C.sub.7-C.sub.13
aralkoxyamine. Even more preferably compound of formula (7a) is
selected from the group consisting of ammonia (NH.sub.3),
hydroxylamine, hydroxylamine-O-sulfonic acid, NH.sub.2OH.HCl,
O-methylhydroxylamine or O-benzylhydroxylamine. Most preferably
compound of formula (7a) is hydroxylamine.
[0061] The second base is selected from the group of compounds
which is able to stabilize an enol moiety derived from the keto
group, in particular in compound of formula (4). The second base of
the present invention includes any strong bulky organic base.
Preferably the second base is selected from the group sodium
tert.-butoxide (NaO-tBu), potassium tert.-butoxide (KO-tBu),
lithium di-isopropyl amide (LDA), triethylamine,
2,6-dimethylpyridine, 1, 5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
lithium-bis(trimethylsilyl)amide (LHMDS). More preferably the
second base is selected from the group lithium di-isopropyl amide
(LDA), trimethylamine, dimethylpyridine and
lithium-bis(trimethylsilyl)amide (LHMDS). Most preferably the
second base is lithium di-isopropyl amide (LDA).
[0062] The third protective reagent is a member of the group of
compounds which is able to form a protective group for hydroxyl
groups and is generally selected as known in the art. Examples of
suitable third protective reagents to obtain protective groups for
hydroxyl groups are described in T. W. Greene, P. G. M. Wutts
"Protective Groups in Organic Synthesis", John Wiley & Sons,
5.sup.th Ed., 2014, pages 17-374. Preferably, the third protective
reagent is selected from the group consisting of alkylsulfate
(CH.sub.3SO.sub.4), alkyliodide (CH.sub.31), diazoalkane
(CH.sub.2N.sub.2), dialkylhydrogenphosphite ((MeO).sub.2POH),
isobutylene (C.sub.4H.sub.8), allylbromide, trimethylchlorosilane
(TMSCl), trimethylsilyltriflate (TMSOTf), trimethylsilylcyanide
(TMSCN), trimethylsilyldiethylamine, triethylsilylchloride (TESCl),
triisopropylsilylchloride (TIPSCl), t-butyldimethylsilylchloride
(TBDMSCl), t-butyldiphenylsilylchloride (TBDPSCl),
tri-iso-propylsilyloxymethylchloride, chloromethylmethylether
(CMME), bromomethylmethylether, iodomethylmethylether,
dimethoxymethane (CH.sub.2(OMe).sub.2), diethoxyethane
(CH.sub.2(OEt).sub.2 (Phenyldimethylsilyl)methoxymethylchloride
(SMOMCl), ethylvinylether, 2-(chloromethoxy)-2-methylpropane
(t-BuOCH.sub.2C1), ((tert-butoxymethyl)sulfonyl)benzene
(t-BuOCH.sub.2SO.sub.2Ph), 4-pentenyloxymethylchloride (POMCl),
2-methoxyethoxymethyl chloride (MEMCl), 2,2,
2-trichloroethoxymethoxychloride,
2,2,2-trichloroethoxymethoxybromide,
(4-methoxyphenoxy)methylchloride (p-AOMCl),
p-methoxybenzyloxymethylchloride (PMBMCl), benzyloxymethylchloride
(PhCH.sub.2OCH.sub.2OCl), p-methoxyphenol, p-methoxybenzyl 2,2,
2-trichloroacetimidate, guaiacolmethylchloride
(2-MeOC.sub.6H.sub.4OCH.sub.2C1), acetic anhydride (Ac.sub.2O),
benzoylchloride (BzCl), benzylbromide, benzylchloride,
iodomethylmethylsulfane (CH.sub.3SHC.sub.2l),
chloromethylmethylsulfane (CH.sub.3SHC.sub.2Cl), dimethylsulfide
(CH.sub.3SCH.sub.3), oxalylchloride (COCl).sub.2, pivaloyl chloride
(PivCl), 3,4-dihydropyran and tritylchloride. More preferably, the
third protective reagent is selected from the group consisting of
trimethylchlorosilane (TMSCl), trimethylsilyltriflate (TMSOTf),
trimethylsilylcyanide (TMSCN), trimethylsilyldiethylamine,
triethylsilylchloride (TESCl), triisopropylsilylchloride (TIPSCl),
t-butyldimethylsilylchloride (TBDMSCl),
t-butyldiphenylsilylchloride (TBDPSCl) and
tri-iso-propylsilyloxymethylchloride. Even more preferably the
third protective reagent is selected from the group consisting of
trimethylchlorosilane (TMSCl), trimethylsilyltriflate (TMSOTf),
trimethylsilylcyanide (TMSCN), trimethylsilyldiethylamine,
triethylsilylchloride (TESCl), triisopropylsilylchloride (TIPSCl),
t-butyldimethylsilylchloride (TBDMSCl) and
t-butyldiphenylsilylchloride (TBDPSCl). Most preferably, the third
protective reagent of the present invention is
t-butyldimethylsilylchloride (TBDMSCl).
[0063] The fourth protective reagent is a member of the group of
compounds which is able to form a protective group for hydroxyl
groups and can be any suitable protective group known in the art.
Examples of suitable fourth protective reagents to obtain
protective groups for hydroxyl groups are described in T. W.
Greene, P. G. M. Wutts "Protective Groups in Organic Synthesis",
John Wiley & Sons, 5.sup.th Ed., 2014, pages 17-374. Preferably
the fourth protective reagent is selected from the group consisting
of alkylsulfate (CH.sub.3SO.sub.4), alkyliodide (CH.sub.31),
diazoalkane (CH.sub.2N.sub.2), dialkylhydrogenphosphite
((MeO).sub.2POH), isobutylene (C.sub.4H.sub.8), allylbromide,
trimethylchlorosilane (TMSCl), trimethylsilyltriflate (TMSOTf),
trimethylsilylcyanide (TMSCN), trimethylsilyldiethylamine,
triethylsilylchloride (TESCl), triisopropylsilylchloride (TIPSCl),
t-butyldimethylsilylchloride (TBDMSCl),
t-butyldiphenylsilylchloride (TBDPSCl),
tri-iso-propylsilyloxymethylchloride, chloromethylmethylether
(CMME), bromomethylmethylether, iodomethylmethylether,
dimethoxymethane (CH.sub.2(OMe).sub.2), diethoxyethane
(CH.sub.2(OEt).sub.2 (Phenyldimethylsilyl)methoxymethylchloride
(SMOMCl), ethylvinylether, 2-(chloromethoxy)-2-methylpropane
(t-BuOCH.sub.2Cl), ((tert-butoxymethyl)sulfonyl)benzene
(t-BuOCH.sub.2SO.sub.2Ph), 4-pentenyloxymethylchloride (POMCl),
2-methoxyethoxymethyl chloride (MEMCl), 2,2,
2-trichloroethoxymethoxychloride,
2,2,2-trichloroethoxymethoxybromide,
(4-methoxyphenoxy)methylchloride (p-AOMCl),
p-methoxybenzyloxymethylchloride (PMBMCl), benzyloxymethylchloride
(PhCH.sub.2OCH.sub.2OCl), p-methoxyphenol, p-methoxybenzyl 2,2,
2-trichloroacetimidate, guaiacolmethylchloride
(2-MeOC.sub.6H.sub.4OCH.sub.2Cl), acetic anhydride (Ac.sub.2O),
benzoylchloride (BzCl), benzylbromide, benzylchloride,
iodomethylmethylsulfane (CH.sub.3SHC.sub.2l),
chloromethylmethylsulfane (CH.sub.3SHC.sub.2Cl), dimethylsulfide
(CH.sub.3SCH.sub.3), oxalylchloride (COCl).sub.2, pivaloyl chloride
(PivCl), 3,4-dihydropyran or tritylchloride. More preferably, the
fourth protective reagent of the present invention is selected from
the group consisting of trimethylchlorosilane (TMSCl),
trimethylsilyltriflate (TMSOTf), trimethylsilylcyanide (TMSCN),
trimethylsilyldiethylamine, triethylsilylchloride (TESCl),
triisopropylsilylchloride (TIPSCl), t-butyldimethylsilylchloride
(TBDMSCl), t-butyldiphenylsilylchloride (TBDPSCl), or
tri-iso-propylsilyloxymethylchloride. Even more preferably the
fourth protective reagent in the present invention is selected from
the group consisting of trimethylchlorosilane (TMSCl),
trimethylsilyltriflate (TMSOTf), trimethylsilylcyanide (TMSCN),
trimethylsilyldiethylamine, triethylsilylchloride (TESCl),
triisopropylsilylchloride (TIPSCl), t-butyldimethylsilylchloride
(TBDMSCl), t-butyldiphenylsilylchloride (TBDPSCl). Most preferably,
the fourth protective reagent of the present invention is
t-butyldimethylsilylchloride (TBDMSCl).
[0064] The third oxidizing agent is any sutable oxidizing agent
capable of either transforming a keto group as present in compound
of formula (4) or an enol moiety as present in compound of formula
(5) to the corresponding secondary alpha-hydroxy-ketone moiety of
compound of formula (6). Optionally, the third oxidizing agent is a
is an oxidizing agent furthermore capable of transforming the
alpha-hydroxy-ketone moiety of compound of formula (6) into two
separated functional groups, i.e. an aldehyde and a carboxylic
acid, linked to different cyclic moieties as present in compound of
formula (7). Preferably, the third oxidizing agent of the invention
is selected from the group consisting of potassium
peroxymonosulfate (KHSO.sub.5), oxaziridine, ozone, peroxyacid,
hydrogen peroxide and hypofluorous acid (HOF). More preferably the
third oxidazing agent of the invention is selected from the group
consisting of potassium peroxymonosulfate (KHSO5),
sulfonyloaziridine or Davis' chiral oxaziridine, ozone, a
peroxyacid, hydrogen peroxide or hypofluorous acid (HOF). Even more
preferably, the third oxidizing agent of the invention is selected
from the group consisting of potassium peroxymonosulfate
(KHSO.sub.5), peroxyacid and hydrogen peroxide. Even more
preferably the third oxidizing agent of the invention is selected
from the group consisting of potassium peroxymonosulfate
(KHSO.sub.5), meta-chloroperoxybenzoic acid (mCPBA) and hydrogen
peroxide. Most preferably, the third oxiziding agent of the
invention is meta-chloroperoxybenzoic acid (mCPBA).
[0065] The fourth oxidizing agent is an oxidizing agent capable of
transforming the alpha-hydroxy-ketone moiety of compound of formula
(6) into two separated functional groups, i.e. an aldehyde and a
carboxylic acid, linked to separate cyclic moieties as present in
compound of formula (7). Examples of the fourth oxidizing agent of
the present invention include percarbonates, periodates, lead
tetraacetate (LTA), osmium complexes, bismuthate, bismuth(III)
carboxylates, iodo triacetate, manganic pyrophosphate, manganese
dioxide, potassium peroxymonosulfate (KHSO.sub.5), calcium
hypochlorite, basic hydrogen peroxide, methylrhenium trioxide,
chromium(VI) reagents, ceric ammonium nitrate and vanadium-based
heteropolyacids (HPA). Preferably, the fourth oxidizing agent of
the invention is selected from the group consisting of sodium
percarbonate, sodium metaperiodate (NalO.sub.4), lead tetraacetate
(LTA), sodium bismuthate (NaBiO.sub.3), bismuth(III)mandelate, iodo
triacetate, manganic pyrophosphate, manganese dioxide, potassium
peroxymonosulfate (KHSO.sub.5) and calcium hypochlorite. More
preferably the fourth oxidizing agent of the invention is selected
from the group consisting of sodium percarbonate, sodium
metaperiodate (NalO.sub.4), lead tetraacetate (LTA) and potassium
peroxymonosulfate (KHSO.sub.5). Even more preferably, the fourth
oxidizing agent of the invention is selected from the group
consisting of sodium metaperiodate and lead tetraacetate (LTA).
Most preferably, the fourth oxidizing agent of the invention is
sodium metaperiodate (NalO.sub.4).
[0066] "Heteropolyacid" generally refers to an acid made up of a
particular combination of hydrogen and oxygen with certain metals
and non-metals. To qualify as a heteropoly acid, the compound must
typically contain a metal such as tungsten, molybdenum or vanadium,
termed the addenda atom, oxygen, an element generally from the
p-block of the periodic table, such as silicon, phosphorus or
arsenic, termed the hetero atom and acidic hydrogen atoms. The
metal addenda atoms linked by oxygen atoms typically form a cluster
with the hetero-atom inside bonded via oxygen atoms. Examples with
more than one type of metal addenda atom in the cluster are well
known.
[0067] Contacting the compound of formula (4) with a second base
and a third protective reagent to form a compound of formula (5)
may be performed in the presence of a solvent or a mixture of
solvents. Suitable solvents include anhydrous tetrahydrofuran
(THF), 2-methyltetrahydrofuran MeTHF, ether, dioxane,
dimethoxyethane (DME), heptane, toluene, xylene or benzene.
Preferably the solvent is selected from the group consisting of
tetrahydrofuran (THF), diethyl ether, 1,4-dioxane, heptane and
ethylbenzene or mixtures thereof. More preferably the solvent is
selected from the group consisting of tetrahydrofuran (THF),
diethyl ether, heptane and ethylbenzene or mixtures thereof. Most
preferably the solvent is tetrahydrofuran (THF).
[0068] For contacting the compound of formula (4) with a second
base and a third protective reagent to form a compound of formula
(5) the molar ratio of the third protective reagent and compound of
formula (4) is typically at least 0.8, preferably at least 0.9, and
most preferably at least 1, and generally at most 2, preferably at
most 1.8, even more preferably at most 1.6 and most preferably at
most 1.5.
[0069] A suitable temperature for contacting the compound of
formula (4) with a second base and a third protective reagent to
form a compound of formula (5) is preferably at least -85.degree.
C., more preferably at least -80.degree. C., even more preferably
at least -75.degree. C. and most preferably at least -70.degree. C.
A suitable temperature at step i. is preferably at most 50.degree.
C., more preferably at most 40.degree. C., even more preferably at
most 30.degree. C. and most preferably at most 25.degree. C.
[0070] Solvents, suitable for contacting the compound of formula
(4) with a second base and a third oxidizing agent disclosed in
step iii. include organic solvents or mixtures of organic solvents
with water. Preferably, suitable solvents are selected from the
group consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably the solvent is tetrahydrofuran
(THF).
[0071] Solvents, suitable for contacting the compound of formula
(5) with a third oxidizing agent as disclosed in step i. or ii.
include organic solvents or mixtures of organic solvents with
water. Preferably, suitable solvents are selected from the group
consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably, the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably, the solvent is dichloromethane
(DCM).
[0072] For contacting compound of formula (5) with a third
oxidizing agent as disclosed in step i. the molar ratio of the
third oxidizing agent and compound of formula (5) is typically at
least 0.8, preferably at least 0.9, and most preferably at least 1,
and generally at most 2, preferably at most 1.8, even more
preferably at most 1.6, even more preferably at most 1.4 and most
preferably at most 1.3.
[0073] For contacting the compound of formula (4) with a third
oxidizing agent as disclosed in step ii. the molar ratio of the
third oxidizing agent and compound of formula (4) is typically at
least 0.8, preferably at least 0.9, and most preferably at least 1,
and generally at most 1.5, preferably at most 1.4 and most
preferably at most 1.3.
[0074] For contacting the compound of formula (4) with a third
oxidizing agent as disclosed in step iii. the molar ratio of the
third oxidizing agent and compound of formula (4) is typically at
least 1.5, preferably at least 1.7, and most preferably at least 2,
and generally at most 3, preferably at most 2.8, even more
preferably at most 2.6 and most preferably at most 2.5.
[0075] A suitable temperature for contacting the compound of
formula (4) with a base and a third oxidizing agent or contacting
the compound of formula (5) with a third oxidizing agent is
preferably at least -30.degree. C., more preferably at least
-20.degree. C., even more preferably at least -10.degree. C. and
most preferably at least -5.degree. C., and preferably at most
60.degree. C., more preferably at most 50.degree. C., even more
preferably at most 45.degree. C. and most preferably at most
25.degree. C.
[0076] In case R.sup.5 in compound of formula (6) shall be a
protective group, a fourth protective reagent may be added to the
compound obtained from either contacting a compound of formula (4)
with a second base and a third oxidizing agent or contacting a
compound of formula (5) with a third oxidizing agent. The molar
ratio of the fourth protective reagent and the compound obtained
from either contacting a compound of formula (4) with a second base
and a third oxidizing agent or contacting a compound of formula (5)
with a third oxidizing agent of formula (6) is typically at least
0.8, preferably at least 0.9, and most preferably at least 1, and
generally at most 2, preferably at most 1.8, even more preferably
at most 1.6 and most preferably at most 1.5.
[0077] In steps i. and ii. of the invention a compound of formula
(6) is contacted with a fourth oxidizing agent to obtain a compound
of formula (7).
[0078] The fourth oxidizing agent is a member of the group of
compounds which is able to transform the alpha-hydroxy-ketone
moiety of compound of formula (6) into two separated functional
groups, i.e. an aldehyde and a carboxylic acid, linked to separate
cyclic moieties as present in compound of formula (7).
[0079] Suitable fourth oxidizing agents of the present invention
include percarbonates, perjodates, lead tetraacetate (LTA), osmium
complexes, bismuthate, bismuth(III) carboxylates, iodo triacetate,
manganic pyrophosphate, manganese dioxide, potassium
peroxymonosulfate (KHSO.sub.5), calcium hypochlorite, basic
hydrogen peroxide, methylrhenium trioxide, chromium(VI) reagents,
ceric ammonium nitrate and vanadium-based heteropolyacids (HPA).
Preferably, the fourth oxidizing agent of the invention is selected
from the group consisting of sodium percarbonate, sodium
metaperiodate (NalO.sub.4), lead tetraacetate (LTA), sodium
bismuthate (NaBiO.sub.3), bismuth(III)mandelate, iodo triacetate,
manganic pyrophosphate, manganese dioxide, potassium
peroxymonosulfate (KHSO.sub.5) and calcium hypochlorite, ore
preferably from the group consisting of sodium percarbonate, sodium
metaperiodate (NalO.sub.4), lead tetraacetate (LTA) and potassium
peroxymonosulfate (KHSO.sub.5), even more preferably from the group
consisting of sodium metaperiodate and lead tetraacetate (LTA).
Most preferably, the fourth oxidizing agent of the invention is
sodium metaperiodate (NalO.sub.4).
[0080] Contacting compound of formula (6) with a fourth oxidizing
agent to obtain a compound of formula (7) may be performed in the
presence or absence of a solvent or mixture of solvents.
[0081] Solvents, suitable for contacting compound of formula (6)
with a fourth oxidizing agent to obtain a compound of formula (7)
include organic solvents or mixtures of organic solvents with
water. Preferably, the solvent suitable for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) are selected from the group consisting of methanol
(MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF),
dichloromethane (DCM), chloroform (CHCl.sub.3), toluene, xylene and
benzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of methanol (MeOH) and dimethyl
sulfoxide (DMSO) or mixtures thereof. Most preferably, the solvent
is methanol (MeOH).
[0082] For contacting compound of formula (6) with a fourth
oxidizing agent to obtain a compound of formula (7) the molar ratio
of the fourth oxidizing agent and compound of formula (6) is
typically between 1 and 3. Preferably, for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) the molar ratio of the fourth oxidizing agent and
compound of formula (6) is preferably at least 1.6, more preferably
at least 1.8, most preferably at least 2, and preferably at most
2.8, more preferably at most 2.5 and most preferably at most
2.3.
[0083] A suitable temperature for contacting compound of formula
(6) with a fourth oxidizing agent to obtain a compound of formula
(7) is preferably at least 0.degree. C., more preferably at least
10.degree. C., even more preferably at least 15.degree. C. and most
preferably at least 20.degree. C. A suitable temperature for
contacting compound of formula (6) with a fourth oxidizing agent to
obtain a compound of formula (7) is preferably at most 60.degree.
C., more preferably at most 50.degree. C., even more preferably at
most 45.degree. C. and most preferably at most 30.degree. C.
[0084] The step of contacting the compound of formula (7) with a
compound of formula (7a) to obtain a compound of formula (8) may be
performed in the presence of a solvent or mixture of solvents.
Suitable solvents include water, organic solvents or mixtures of
organic solvents with water. Preferably, the solvent in the step of
contacting the compound of formula (7) with a compound of formula
(7a) to obtain a compound of formula (8) is selected from the group
consisting of water, methanol, ethanol, 1-butanol, 2-butanol,
1,2-dimethoxy-ethane (DME), tetrahydrofuran (THF) and 1,4-dioxane.
More preferably, the solvent is selected from the group consisting
of water, methanol, ethanol and tetrahydrofuran (THF) or mixtures
thereof. Most preferably, the solvent is tetrahydrofuran (THF).
[0085] The molar ratio of compound of formula (7) and compound of
formula (7a) when contacting compound of formula (7) with compound
of formula (7a) to obtain a compound of formula (8) is typically at
least 0.8, preferably at least 0.9, and most preferably at least 1,
and generally at most 1.5, preferably at most 1.4 and most
preferably at most 1.3.
[0086] The temperature at the step of contacting compound of
formula (7) with compound of formula (7a) to obtain a compound of
formula (8) is preferably at least 0.degree. C., more preferably at
least 10.degree. C., even more preferably at least 15.degree. C.
and most preferably at least 20.degree. C. The temperature at the
step of contacting compound of formula (7) with compound of formula
(7a) to obtain a compound of formula (8) is preferably at most
90.degree. C., more preferably at most 70.degree. C., even more
preferably at most 50.degree. C. and most preferably at most
35.degree. C.
[0087] The compound of formula (8) is contacted with a reducing
agent to obtain the compound of formula (9).
[0088] The reducing agent is a member of the group of compounds
which is able to transform the imino group of compound of formula
(8) into an amine as present in compound of formula (8).
Preferably, the reducing agent is selected from the group
consisting of hydrogen or an ionic or a metallic hydride. More
preferably, the reducing agent is selected from the group
consisting of hydrogen, alane (AlH.sub.3), lithium aluminium
hydride (LiAlH.sub.4), sodium hydride (NaH) and
diisobutylaluminiumhydride (DIBAL-H), even more preferably selected
from the group consisting of hydrogen, alane (AlH.sub.3), lithium
aluminium hydride (LiAlH.sub.4) and diisobutylaluminiumhydride
(DIBAL-H) and most preferably the reducing agent is alane
(AlH.sub.3).
[0089] In case hydrogen is selected as reducing agent, catalysts
may be present as known in the art. Examples of such catalysts
include Ni, Co, Pd, Pt, Ru, Rh, Os, Ir, Os and Fe.
[0090] The step of contacting compound of formula (8) with a
reducing agent to obtain the compound of formula (9) may be
performed at atmospheric or elevated pressure. Preferably, the
transformation is performed at atmospheric pressure.
[0091] Solvents, suitable for the step of contacting compound of
formula (8) with a reducing agent to obtain the compound of formula
(9) include organic solvents or mixtures of organic solvents.
Preferably, the solvent for the step of contacting compound of
formula (8) with a reducing agent to obtain the compound of formula
(9) is selected from the group consisting of 1,2-dimethoxy-ethane
(DME), tetrahydrofuran (THF), chloroform (CHCl.sub.3), toluene and
benzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of tetrahydrofuran (THF) and
toluene or mixtures thereof. Most preferably, the solvent is
tetrahydrofuran (THF).
[0092] The invention further pertains to a process comprising
contacting the compound of formula (4)
##STR00022##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
second base and a third protective reagent to form a compound of
formula (5)
##STR00023##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are protective
groups. R.sup.1, R.sup.2, R.sup.3, R.sup.4, the second base and the
third protective reagent are selected as described above.
[0093] Contacting the compound of formula (4) with a second base
and a third protective reagent to form a compound of formula (5)
may be performed in the presence of a solvent or a mixture of
solvents. Suitable solvents include anhydrous tetrahydrofuran
(THF), 2-methyltetrahydrofuran MeTHF, ether, dioxane,
dimethoxyethane (DME), heptane, toluene, xylene or benzene.
Preferably, the solvent is selected from the group consisting of
tetrahydrofuran (THF), diethyl ether, 1,4-dioxane, heptane and
ethylbenzene or mixtures thereof. More preferably the solvent is
selected from the group consisting of tetrahydrofuran (THF),
diethyl ether, heptane and ethylbenzene or mixtures thereof. Most
preferably, the solvent is tetrahydrofuran (THF).
[0094] For contacting the compound of formula (4) with a second
base and a third protective reagent to form a compound of formula
(5) the molar ratio of the third protective reagent and compound of
formula (4) is typically at least 0.8, preferably at least 0.9, and
most preferably at least 1, and generally at most 2, preferably at
most 1.8, even more preferably at most 1.6 and most preferably at
most 1.5.
[0095] A suitable temperature for contacting the compound of
formula (4) with a second base and a third protective reagent to
form a compound of formula (5) is preferably at least -85.degree.
C., more preferably at least -80.degree. C., even more preferably
at least -75.degree. C. and most preferably at least -70.degree. C.
A suitable temperature at step i. is preferably at most 50.degree.
C., more preferably at most 40.degree. C., even more preferably at
most 30.degree. C. and most preferably at most 25.degree. C.
[0096] The invention further pertains to a process comprising
contacting compound of formula (5)
##STR00024##
wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are protective
groups, with a third oxidizing agent and optionally with a fourth
protective reagent to obtain a compound of formula (6)
##STR00025##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups and
R.sup.5 is H or a protective group. R.sup.1, R.sup.2, R.sup.3,
R.sup.5, the third oxidizing agent and the fourth protective
reagent are as described above.
[0097] Solvents, suitable for contacting the compound of formula
(5) with a third oxidizing agent to obtain a compound of formula
(6) include organic solvents or mixtures of organic solvents with
water. Preferably, suitable solvents are selected from the group
consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably, the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably, the solvent is dichloromethane
(DCM).
[0098] For contacting compound of formula (5) with a third
oxidizing agent to obtain a compound of formula (6) the molar ratio
of the third oxidizing agent and compound of formula (5) is
typically at least 0.8, preferably at least 0.9, and most
preferably at least 1, and generally at most 2, preferably at most
1.8, even more preferably at most 1.6, even more preferably at most
1.4 and most preferably at most 1.3.
[0099] A suitable temperature for contacting the compound of
formula (5) with a third oxidizing agent to obtain a compound of
formula (6) is preferably at least -30.degree. C., more preferably
at least -20.degree. C., even more preferably at least -10.degree.
C. and most preferably at least -5.degree. C., and preferably at
most 60.degree. C., more preferably at most 50.degree. C., even
more preferably at most 45.degree. C. and most preferably at most
25.degree. C.
[0100] In case R.sup.5 in compound of formula (6) shall be a
protective group, a fourth protective reagent may be added to the
compound obtained from contacting a compound of formula (5) with a
third oxidizing agent. The molar ratio of the fourth protective
reagent and the compound obtained from contacting a compound of
formula (5) with a third oxidizing agent is typically at least 0.8,
preferably at least 0.9, and most preferably at least 1, and
generally at most 2, preferably at most 1.8, even more preferably
at most 1.6 and most preferably at most 1.5.
[0101] The invention further pertains to a process comprising
contacting compound of formula (6)
##STR00026##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups and
R.sup.5 is H or a protective group, with a fourth oxidizing agent
to obtain the compound of formula (7)
##STR00027##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups.
R.sup.1, R.sup.2, R.sup.3, and the fourth oxidizing agent are
selected as described above.
[0102] Contacting compound of formula (6) with a fourth oxidizing
agent to obtain a compound of formula (7) may be performed in the
presence or absence of a solvent or mixture of solvents.
[0103] Solvents, suitable for contacting compound of formula (6)
with a fourth oxidizing agent to obtain a compound of formula (7)
include organic solvents or mixtures of organic solvents with
water. Preferably, the solvent suitable for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) are selected from the group consisting of methanol
(MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF),
dichloromethane (DCM), chloroform (CHCl.sub.3), toluene, xylene and
benzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of methanol (MeOH) and dimethyl
sulfoxide (DMSO) or mixtures thereof. Most preferably, the solvent
is methanol (MeOH).
[0104] For contacting compound of formula (6) with a fourth
oxidizing agent to obtain a compound of formula (7) the molar ratio
of the fourth oxidizing agent and compound of formula (6) is
typically between 1 and 3. Preferably, for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) the molar ratio of the fourth oxidizing agent and
compound of formula (6) is preferably at least 1.6, more preferably
at least 1.8, most preferably at least 2, and preferably at most
2.8, more preferably at most 2.5 and most preferably at most
2.3.
[0105] A suitable temperature for contacting compound of formula
(6) with a fourth oxidizing agent to obtain a compound of formula
(7) is preferably at least 0.degree. C., more preferably at least
10.degree. C., even more preferably at least 15.degree. C. and most
preferably at least 20.degree. C. A suitable temperature for
contacting compound of formula (6) with a fourth oxidizing agent to
obtain a compound of formula (7) is preferably at most 60.degree.
C., more preferably at most 50.degree. C., even more preferably at
most 45.degree. C. and most preferably at most 30.degree. C.
[0106] The invention further pertains to a process comprising
contacting the compound of formula (4)
##STR00028##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
second base and a third protective reagent to form a compound of
formula (5)
##STR00029##
wherein R.sup.4 is a protective group, and contacting the compound
of formula (5) with a third oxidizing agent and optionally with a
fourth protective reagent to obtain a compound of formula (6)
##STR00030##
wherein R.sup.5 is H or a protective group; and contacting the
compound of formula (6) with a fourth oxidizing agent to obtain the
compound of formula (7).
##STR00031##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups.
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, the second base, the
second protective reagent, the third oxidizing agent, the fourth
protective reagent and the fourth oxidizing agent are selected as
described above.
[0107] Contacting the compound of formula (4) with a second base
and a third protective reagent to form a compound of formula (5)
may be performed in the presence of a solvent or a mixture of
solvents. Suitable solvents include anhydrous tetrahydrofuran
(THF), 2-methyltetrahydrofuran MeTHF, ether, dioxane,
dimethoxyethane (DME), heptane, toluene, xylene or benzene.
Preferably, the solvent is selected from the group consisting of
tetrahydrofuran (THF), diethyl ether, 1,4-dioxane, heptane and
ethylbenzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of tetrahydrofuran (THF),
diethyl ether, heptane and ethylbenzene or mixtures thereof. Most
preferably, the solvent is tetrahydrofuran (THF).
[0108] For contacting the compound of formula (4) with a second
base and a third protective reagent to form a compound of formula
(5) the molar ratio of the third protective reagent and compound of
formula (4) is typically at least 0.8, preferably at least 0.9, and
most preferably at least 1, and generally at most 2, preferably at
most 1.8, even more preferably at most 1.6 and most preferably at
most 1.5.
[0109] A suitable temperature for contacting the compound of
formula (4) with a second base and a third protective reagent to
form a compound of formula (5) is preferably at least -85.degree.
C., more preferably at least -80.degree. C., even more preferably
at least -75.degree. C. and most preferably at least -70.degree. C.
A suitable temperature at step i. is preferably at most 50.degree.
C., more preferably at most 40.degree. C., even more preferably at
most 30.degree. C. and most preferably at most 25.degree. C.
[0110] Solvents, suitable for contacting the compound of formula
(4) with a third oxidizing agent include organic solvents or
mixtures of organic solvents with water. Preferably, suitable
solvents are selected from the group consisting of tetrahydrofuran
(THF), dichloromethane (DCM), chloroform (CHCl.sub.3), toluene and
benzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of tetrahydrofuran (THF),
dichloromethane (DCM) and toluene or mixtures thereof. Most
preferably, the solvent is dichloromethane (DCM).
[0111] For contacting the compound of formula (4) with a third
oxidizing agent the molar ratio of the third oxidizing agent and
compound of formula (4) is typically at least 0.8, preferably at
least 0.9, and most preferably at least 1, and generally at most
1.5, preferably at most 1.4 and most preferably at most 1.3.
[0112] A suitable temperature for contacting the compound of
formula (4) with a third oxidizing agent is preferably at least
-30.degree. C., more preferably at least -20.degree. C., even more
preferably at least -10.degree. C. and most preferably at least
-5.degree. C., and preferably at most 60.degree. C., more
preferably at most 50.degree. C., even more preferably at most
45.degree. C. and most preferably at most 25.degree. C.
[0113] Solvents, suitable for contacting the compound of formula
(5) with a third oxidizing agent to obtain a compound of formula
(6) include organic solvents or mixtures of organic solvents with
water. Preferably, suitable solvents are selected from the group
consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably the solvent is dichloromethane
(DCM).
[0114] For contacting compound of formula (5) with a third
oxidizing agent to obtain a compound of formula (6) the molar ratio
of the third oxidizing agent and compound of formula (5) is
typically at least 0.8, preferably at least 0.9, and most
preferably at least 1, and generally at most 2, preferably at most
1.8, even more preferably at most 1.6, even more preferably at most
1.4 and most preferably at most 1.3.
[0115] A suitable temperature for contacting the compound of
formula (5) with a third oxidizing agent to obtain a compound of
formula (6) is preferably at least -30.degree. C., more preferably
at least -20.degree. C., even more preferably at least -10.degree.
C. and most preferably at least -5.degree. C., and preferably at
most 60.degree. C., more preferably at most 50.degree. C., even
more preferably at most 45.degree. C. and most preferably at most
25.degree. C.
[0116] In case R.sup.5 in the compound of formula (6) shall be a
protective group, a fourth protective reagent may be added to the
compound obtained from contacting a compound of formula (5) with a
third oxidizing agent. The molar ratio of the fourth protective
reagent and the compound obtained from contacting a compound of
formula (5) with a third oxidizing agent is typically at least 0.8,
preferably at least 0.9, and most preferably at least 1, and
generally at most 2, preferably at most 1.8, even more preferably
at most 1.6 and most preferably at most 1.5.
[0117] Contacting the compound of formula (6) with a fourth
oxidizing agent to obtain the compound of formula (7) may be
performed in the presence or absence of a solvent or mixture of
solvents.
[0118] Solvents, suitable for contacting the compound of formula
(6) with a fourth oxidizing agent to obtain the compound of formula
(7) include organic solvents or mixtures of organic solvents with
water. Preferably, the solvent suitable for contacting the compound
of formula (6) with a fourth oxidizing agent to obtain the compound
of formula (7) are selected from the group consisting of methanol
(MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF),
dichloromethane (DCM), chloroform (CHCl.sub.3), toluene, xylene and
benzene or mixtures thereof. More preferably, the solvent is
selected from the group consisting of methanol (MeOH) and dimethyl
sulfoxide (DMSO) or mixtures thereof. Most preferably, the solvent
is methanol (MeOH).
[0119] For contacting the compound of formula (6) with a fourth
oxidizing agent to obtain the compound of formula (7) the molar
ratio of the fourth oxidizing agent and the compound of formula (6)
is typically between 1 and 3. Preferably, for contacting the
compound of formula (6) with a fourth oxidizing agent to obtain the
compound of formula (7) the molar ratio of the fourth oxidizing
agent and the compound of formula (6) is preferably at least 1.6,
more preferably at least 1.8, most preferably at least 2, and
preferably at most 2.8, more preferably at most 2.5 and most
preferably at most 2.3.
[0120] A suitable temperature for contacting the compound of
formula (6) with a fourth oxidizing agent to obtain the compound of
formula (7) is preferably at least 0.degree. C., more preferably at
least 10.degree. C., even more preferably at least 15.degree. C.
and most preferably at least 20.degree. C. A suitable temperature
for contacting compound of formula (6) with a fourth oxidizing
agent to obtain the compound of formula (7) is preferably at most
60.degree. C., more preferably at most 50.degree. C., even more
preferably at most 45.degree. C. and most preferably at most
30.degree. C.
[0121] The invention further pertains to a process comprising
contacting the compound of formula (4)
##STR00032##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
second base and a third oxidizing agent and optionally with a
fourth protective reagent to obtain a compound of formula (6),
wherein the molar ratio of the third oxidizing agent and the
compound of formula (4) is at most 1.5; and contacting a compound
of formula (6)
##STR00033##
wherein R.sup.5 is H or a protective group, with a fourth oxidizing
agent to obtain the compound of formula (7). R.sup.1, R.sup.2,
R.sup.3, R.sup.5, the second base, the second protective reagent,
the third oxidizing agent, the fourth protective reagent and the
fourth oxidizing agent are selected as described above.
[0122] Solvents, suitable for contacting the compound of formula
(4) with a second base and a third oxidizing agent include organic
solvents or mixtures of organic solvents with water. Preferably,
suitable solvents are selected from the group consisting of
tetrahydrofuran (THF), dichloromethane (DCM), chloroform
(CHCl.sub.3), toluene and benzene or mixtures thereof. More
preferably the solvent is selected from the group consisting of
tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably the solvent is dichloromethane
(DCM).
[0123] For contacting the compound of formula (4) with a second
base and a third oxidizing agent the molar ratio of the third
oxidizing agent and compound of formula (4) is typically at least
0.8, preferably at least 0.9, and most preferably at least 1, and
generally at most 1.5, preferably at most 1.4 and most preferably
at most 1.3.
[0124] A suitable temperature for contacting the compound of
formula (4) with a base and a third oxidizing agent is preferably
at least -30.degree. C., more preferably at least -20.degree. C.,
even more preferably at least -10.degree. C. and most preferably at
least -5.degree. C., and preferably at most 60.degree. C., more
preferably at most 50.degree. C., even more preferably at most
45.degree. C. and most preferably at most 25.degree. C.
[0125] In case R.sup.5 in compound of formula (6) shall be a
protective group, a fourth protective reagent may be added to the
compound obtained from either contacting a compound of formula (4)
with a second base and a third oxidizing agent or contacting a
compound of formula (5) with a third oxidizing agent. The molar
ratio of the fourth protective reagent and the compound obtained
from either contacting a compound of formula (4) with a second base
and a third oxidizing agent or contacting a compound of formula (5)
with a third oxidizing agent of formula (6) is typically at least
0.8, preferably at least 0.9, and most preferably at least 1, and
generally at most 2, preferably at most 1.8, even more preferably
at most 1.6 and most preferably at most 1.5.
[0126] The invention further pertains to a process comprising
contacting the compound of formula (4)
##STR00034##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
second base and a third oxidizing agent to obtain the compound of
formula (7)
##STR00035##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups and
wherein the molar ratio of the third oxidizing agent and the
compound of formula (4) is at least 1.5 R.sup.1, R.sup.2, R.sup.3,
the second base, and the third oxidizing agent are selected as
described above.
[0127] Solvents, suitable for contacting the compound of formula
(4) with a second base and a third oxidizing agent to obtain the
compound of formula (7) include organic solvents or mixtures of
organic solvents with water. Preferably, suitable solvents are
selected from the group consisting of tetrahydrofuran (THF),
dichloromethane (DCM), chloroform (CHCl.sub.3), toluene and benzene
or mixtures thereof. More preferably the solvent is selected from
the group consisting of tetrahydrofuran (THF), dichloromethane
(DCM) and toluene or mixtures thereof. Most preferably the solvent
is tetrahydrofuran (THF).
[0128] For contacting the compound of formula (4) with a third
oxidizing agent to obtain the compound of formula (7) the molar
ratio of the third oxidizing agent and compound of formula (4) is
typically at least 1.5, preferably at least 1.7, and most
preferably at least 2, and generally at most 3, preferably at most
2.8, even more preferably at most 2.6 and most preferably at most
2.5.
[0129] A suitable temperature for contacting the compound of
formula (4) with a base and a third oxidizing agent to obtain the
compound of formula (7) is preferably at least -30.degree. C., more
preferably at least -20.degree. C., even more preferably at least
-10.degree. C. and most preferably at least -5.degree. C., and
preferably at most 60.degree. C., more preferably at most
50.degree. C., even more preferably at most 45.degree. C. and most
preferably at most 25.degree. C.
[0130] The invention further pertains to a process comprising
converting the compound of formula (4) to a compound of formula
(7)
##STR00036##
comprising the steps selected from: [0131] i) contacting the
compound of formula (4) with a second base and a third protective
reagent to form a compound of formula (5)
[0131] ##STR00037## [0132] wherein R.sup.4 is a protective group,
and [0133] contacting the compound of formula (5) with a third
oxidizing agent and optionally with a fourth protective reagent to
obtain a compound of formula (6)
[0133] ##STR00038## [0134] wherein R.sup.5 is H or a protective
group; and [0135] contacting the compound of formula (6) with a
fourth oxidizing agent to obtain the compound of formula (7);
or
[0136] ii) contacting the compound of formula (4) with a second
base and a third oxidizing agent and optionally with a fourth
protective reagent to obtain a compound of formula (6), wherein the
molar ratio of the third oxidizing agent and the compound of
formula (4) is at most 1.5; and [0137] contacting a compound of
formula (6) with a fourth oxidizing agent to obtain the compound of
formula (7); or
[0138] iii) contacting the compound of formula (4) with a second
base and a third oxidizing agent and optionally with a fourth
protective reagent to obtain the compound of formula (7), wherein
the molar ratio of the third oxidizing agent and the compound of
formula (4) is at least 1.5.
R.sup.1, R.sup.2, R.sup.3,R.sup.4, R.sup.5, the second base, the
third protective reagent, the third oxidizing agent, the fourth
protective reagent and the fourth oxidizing agent are selected as
described above.
[0139] Contacting the compound of formula (4) with a second base
and a third protective reagent to form the compound of formula (5)
may be performed in the presence of a solvent or a mixture of
solvents. Suitable solvents include anhydrous tetrahydrofuran
(THF), 2-methyltetrahydrofuran MeTHF, ether, dioxane,
dimethoxyethane (DME), heptane, toluene, xylene or benzene.
Preferably the solvent is selected from the group consisting of
tetrahydrofuran (THF), diethyl ether, 1,4-dioxane, heptane and
ethylbenzene or mixtures thereof. More preferably the solvent is
selected from the group consisting of tetrahydrofuran (THF),
diethyl ether, heptane and ethylbenzene or mixtures thereof. Most
preferably the solvent is tetrahydrofuran (THF).
[0140] For contacting the compound of formula (4) with a second
base and a third protective reagent to form the compound of formula
(5) the molar ratio of the third protective reagent and compound of
formula (4) is typically at least 0.8, preferably at least 0.9, and
most preferably at least 1, and generally at most 2, preferably at
most 1.8, even more preferably at most 1.6 and most preferably at
most 1.5.
[0141] A suitable temperature for contacting the compound of
formula (4) with a second base and a third protective reagent to
form a compound of formula (5) is preferably at least -85.degree.
C., more preferably at least -80.degree. C., even more preferably
at least -75.degree. C. and most preferably at least -70.degree. C.
A suitable temperature at step i. is preferably at most 50.degree.
C., more preferably at most 40.degree. C., even more preferably at
most 30.degree. C. and most preferably at most 25.degree. C.
[0142] Solvents, suitable for contacting the compound of formula
(4) with a second base and a third oxidizing agent disclosed in
step iii. include organic solvents or mixtures of organic solvents
with water. Preferably, suitable solvents are selected from the
group consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably, the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably, the solvent is tetrahydrofuran
(THF).
[0143] Solvents, suitable for contacting the compound of formula
(5) with a third oxidizing agent as disclosed in step i. or ii.
include organic solvents or mixtures of organic solvents with
water. Preferably, suitable solvents are selected from the group
consisting of tetrahydrofuran (THF), dichloromethane (DCM),
chloroform (CHCl.sub.3), toluene and benzene or mixtures thereof.
More preferably the solvent is selected from the group consisting
of tetrahydrofuran (THF), dichloromethane (DCM) and toluene or
mixtures thereof. Most preferably the solvent is dichloromethane
(DCM).
[0144] For contacting compound of formula (5) with a third
oxidizing agent as disclosed in step i. the molar ratio of the
third oxidizing agent and compound of formula (5) is typically at
least 0.8, preferably at least 0.9, and most preferably at least 1,
and generally at most 2, preferably at most 1.8, even more
preferably at most 1.6, even more preferably at most 1.4 and most
preferably at most 1.3.
[0145] For contacting the compound of formula (4) with a third
oxidizing agent as disclosed in step ii. the molar ratio of the
third oxidizing agent and compound of formula (4) is typically at
least 0.8, preferably at least 0.9, and most preferably at least 1,
and generally at most 1.5, preferably at most 1.4 and most
preferably at most 1.3.
[0146] For contacting the compound of formula (4) with a third
oxidizing agent as disclosed in step iii. the molar ratio of the
third oxidizing agent and compound of formula (4) is typically at
least 1.5, preferably at least 1.7, and most preferably at least 2,
and generally at most 3, preferably at most 2.8, even more
preferably at most 2.6 and most preferably at most 2.5.
[0147] A suitable temperature for contacting the compound of
formula (4) with a base and a third oxidizing agent or contacting
the compound of formula (5) with a third oxidizing agent is
preferably at least -30.degree. C., more preferably at least
-20.degree. C., even more preferably at least -10.degree. C. and
most preferably at least -5.degree. C., and preferably at most
60.degree. C., more preferably at most 50.degree. C., even more
preferably at most 45.degree. C. and most preferably at most
25.degree. C.
[0148] In case R.sup.5 in compound of formula (6) shall be a
protective group, a fourth protective reagent may be added to the
compound obtained from either contacting a compound of formula (4)
with a second base and a third oxidizing agent or contacting a
compound of formula (5) with a third oxidizing agent. The molar
ratio of the fourth protective reagent and the compound obtained
from either contacting a compound of formula (4) with a second base
and a third oxidizing agent or contacting a compound of formula (5)
with a third oxidizing agent of formula (6) is typically at least
0.8, preferably at least 0.9, and most preferably at least 1, and
generally at most 2, preferably at most 1.8, even more preferably
at most 1.6 and most preferably at most 1.5.
[0149] In steps i. and ii. of the invention a compound of formula
(6) is contacted with a fourth oxidizing agent to obtain a compound
of formula (7).
[0150] The fourth oxidizing agent is a member of the group of
compounds which is able to transform the alpha-hydroxy-ketone
moiety of compound of formula (6) into two separated functional
groups, i.e. an aldehyde and a carboxylic acid, linked to separate
cyclic moieties as present in compound of formula (7).
[0151] Suitable fourth oxidizing agents of the present invention
include percarbonates, perjodates, lead tetraacetate (LTA), osmium
complexes, bismuthate, bismuth(III) carboxylates, iodo triacetate,
manganic pyrophosphate, manganese dioxide, potassium
peroxymonosulfate (KHSO.sub.5), calcium hypochlorite, basic
hydrogen peroxide, methylrhenium trioxide, chromium(VI) reagents,
ceric ammonium nitrate and vanadium-based heteropolyacids (HPA).
Preferably the fourth oxidizing agent of the invention is selected
from the group consisting of sodium percarbonate, sodium
metaperiodate (NalO.sub.4), lead tetraacetate (LTA), sodium
bismuthate (NaBiO.sub.3), bismuth(III)mandelate, iodo triacetate,
manganic pyrophosphate, manganese dioxide, potassium
peroxymonosulfate (KHSO.sub.5) and calcium hypochlorite, ore
preferably from the group consisting of sodium percarbonate, sodium
metaperiodate (NalO.sub.4), lead tetraacetate (LTA) and potassium
peroxymonosulfate (KHSO.sub.5), even more preferably from the group
consisting of sodium metaperiodate and lead tetraacetate (LTA).
Most preferably the fourth oxidizing agent of the invention is
sodium metaperiodate (NalO.sub.4).
[0152] Contacting the compound of formula (6) with a fourth
oxidizing agent to obtain the compound of formula (7) may be
performed in the presence or absence of a solvent or mixture of
solvents.
[0153] Solvents, suitable for contacting the compound of formula
(6) with a fourth oxidizing agent to obtain the compound of formula
(7) include organic solvents or mixtures of organic solvents with
water. Preferably, the solvent suitable for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) are selected from the group consisting of methanol
(MeOH), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF),
dichloromethane (DCM), chloroform (CHCl.sub.3), toluene, xylene and
benzene or mixtures thereof. More preferably the solvent is
selected from the group consisting of methanol (MeOH) and dimethyl
sulfoxide (DMSO) or mixtures thereof. Most preferably the solvent
is methanol (MeOH).
[0154] For contacting the compound of formula (6) with a fourth
oxidizing agent to obtain the compound of formula (7) the molar
ratio of the fourth oxidizing agent and compound of formula (6) is
typically between 1 and 3. Preferably, for contacting compound of
formula (6) with a fourth oxidizing agent to obtain a compound of
formula (7) the molar ratio of the fourth oxidizing agent and
compound of formula (6) is preferably at least 1.6, more preferably
at least 1.8, most preferably at least 2, and preferably at most
2.8, more preferably at most 2.5 and most preferably at most
2.3.
[0155] A suitable temperature for contacting the compound of
formula (6) with a fourth oxidizing agent to obtain the compound of
formula (7) is preferably at least 0.degree. C., more preferably at
least 10.degree. C., even more preferably at least 15.degree. C.
and most preferably at least 20.degree. C. A suitable temperature
for contacting compound of formula (6) with a fourth oxidizing
agent to obtain a compound of formula (7) is preferably at most
60.degree. C., more preferably at most 50.degree. C., even more
preferably at most 45.degree. C. and most preferably at most
30.degree. C.
[0156] The invention further pertains to a process comprising
contacting the compound of formula (7)
##STR00039##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
compound of formula (7a)
NH.sub.2--R.sup.6 (7a)
wherein R.sup.6 is either H or --OR.sup.22, wherein R.sup.22 is
either H or a protective group, to obtain a compound of formula
(8)
##STR00040##
R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are selected as described
above.
[0157] The step of contacting the compound of formula (7) with a
compound of formula (7a) to obtain the compound of formula (8) may
be performed in the presence of a solvent or mixture of solvents.
Suitable solvents include water, organic solvents or mixtures of
organic solvents with water. Preferably the solvent in the step of
contacting the compound of formula (7) with the compound of formula
(7a) to obtain the compound of formula (8) is selected from the
group consisting of water, methanol, ethanol, 1-butanol, 2-butanol,
1,2-dimethoxy-ethane (DME), tetrahydrofuran (THF) and 1,4-dioxane.
More preferably, the solvent is selected from the group consisting
of water, methanol, ethanol and tetrahydrofuran (THF) or mixtures
thereof. Most preferably, the solvent is tetrahydrofuran (THF).
[0158] The molar ratio of the compound of formula (7a) and the
compound of formula (7) when contacting the compound of formula (7)
with compound of formula (7a) to obtain the compound of formula (8)
is typically at least 0.8, preferably at least 0.9, and most
preferably at least 1, and generally at most 1.5, preferably at
most 1.4 and most preferably at most 1.3.
[0159] The temperature at the step of contacting the compound of
formula (7) with the compound of formula (7a) to obtain the
compound of formula (8) is preferably at least 0.degree. C., more
preferably at least 10.degree. C., even more preferably at least
15.degree. C. and most preferably at least 20.degree. C. The
temperature at the step of contacting the compound of formula (7)
with compound of formula (7a) to obtain a compound of formula (8)
is preferably at most 90.degree. C., more preferably at most
70.degree. C., even more preferably at most 50.degree. C. and most
preferably at most 35.degree. C.
[0160] The invention further pertains to a process comprising
contacting the compound of formula (8)
##STR00041##
wherein R.sup.6 is either H or --OR.sup.22, wherein R.sup.22 is
either H or a protective group, with a reducing agent to obtain the
compound of formula (9)
##STR00042##
R.sup.1, R.sup.2, R.sup.3 and R.sup.6 and the reducing agent are
selected as described above.
[0161] The reducing agent is a member of the group of compounds
which is able to transform the imino group of the compound of
formula (8) into an amine as present in the compound of formula
(8). Preferably, the reducing agent is selected from the group
consisting of hydrogen or an ionic or a metallic hydride. More
preferably the reducing agent is selected from the group consisting
of hydrogen, alane (AlH.sub.3), lithium aluminium hydride
(LiAlH.sub.4), sodium hydride (NaH) and diisobutylaluminiumhydride
(DIBAL-H), even more preferably selected from the group consisting
of hydrogen, alane (AlH.sub.3), lithium aluminium hydride
(LiAlH.sub.4)and diisobutylaluminiumhydride (DIBAL-H) and most
preferably the reducing agent is alane (AlH.sub.3).
[0162] In case hydrogen is selected as reducing agent, catalysts
may be present as known in the art. Examples of such catalysts
include Ni, Co, Pd, Pt, Ru, Rh, Os, Ir, Os and Fe.
[0163] The step of contacting the compound of formula (8) with a
reducing agent to obtain the compound of formula (9) may be
performed at atmospheric or elevated pressure. Preferably the
transformation is performed at atmospheric pressure.
[0164] Solvents, suitable for the step of contacting the compound
of formula (8) with a reducing agent to obtain the compound of
formula (9) include organic solvents or mixtures of organic
solvents. Preferably, the solvent for the step of contacting
compound of formula (8) with a reducing agent to obtain the
compound of formula (9) is selected from the group consisting of
1,2-dimethoxy-ethane (DM E), tetrahydrofuran (THF), chloroform
(CHCl.sub.3), toluene and benzene or mixtures thereof. More
preferably, the solvent is selected from the group consisting of
tetrahydrofuran (THF) and toluene or mixtures thereof. Most
preferably, the solvent is tetrahydrofuran (THF).
[0165] The invention further pertains to a process comprising the
step of contacting a compound of formula (9)
##STR00043##
wherein R.sup.1, R.sup.2 and R.sup.3 are protective groups, with a
first acid capable of forming a pharmaceutically acceptable salt
and optionally a fifth protective reagent to obtain the compound of
formula (10)
##STR00044##
wherein R.sup.42 is H or a protective group, R.sup.43 is H or
R.sup.3, wherein R.sup.3 is a protective group, comprising a
counter acid X.sup.1 when R.sup.42.dbd.H and R.sup.43.dbd.H.
R.sup.1, R.sup.2, R.sup.3, R.sup.42 and R.sup.43 are selected as
described above.
[0166] X.sup.1 represents a counter acid which together with the
compounds of the present invention, in particular with compound of
formula (9) may form a pharmaceutically acceptable salt to obtain
compound of formula (10) and which generally may be selected as
known in the art. Examples for the selection of X.sup.1 are
provided by P. H. Stahl and C. G. Wermuth, editors, Handbook of
Pharmaceutical Salts: Properties, Selection and Use,
Weinheim/Zurich:Wiley-VCH/VHCA, 2011. Preferably, X.sup.1 is
selected from the group consisting of any mineral acid and any
organic mono- or di-acid. More preferably, X.sup.1 is selected from
the group consisting of hydrochloric acid, hydrobromic acid,
sulphuric acid, nitric acid, phosphoric acid, acetic acid,
propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic
acid, malonic acid, succinic acid, fumaric acid, tartaric acid,
citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid
and salicylic acid. Even more preferably, X.sup.1 is selected from
the group consisting of acetic acid, benzenesulfonic acid,
hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric
acid, oxalic acid, tartaric acid and p-toluenesulfonic acid. Even
more preferably, X.sup.1 is selected from the group consisting of
benzenesulfonic acid and p-toluenesulfonic acid. Most preferably
X.sup.1 is p-toluenesulfonic acid.
[0167] A first acid represents a counter acid which together with
the compounds of the present invention, in particular with the
compound of formula (9) may form a pharmaceutically acceptable salt
to obtain the compound of formula (10) and which generally may be
selected as known in the art. First acid is equivalent to X.sup.1
and selected accordingly.
[0168] The fifth protective reagent is a member of the group of
compounds which is able to form a protective group for amino groups
and is generally selected as known in the art. Examples of suitable
fifth protective reagents to obtain protective groups for amino
groups are described in T. W. Greene, P. G. M. Wutts "Protective
Groups in Organic Synthesis", John Wiley & Sons, 5.sup.th Ed.,
2014, pages 895-1115. Preferably, the fifth protective reagent is
selected from the group consisting of methyl chloroformate,
fluorenylmethyloxycarbonyl chloride (Fmoc-Cl),
1,1-dioxobenzo[b]thiophen-2-ylmethyl chloroformate,
2-(trimethylsilyl)ethyl chloroformate, 2-phenylethyl chloroformate,
di-tert-butyldicarbonat, 1-adamantyl chloroformate (1-Adoc-Cl),
2-adamantyl chloroformate (2-Adoc-Cl), benzyl bromide, acetic
anhydride, acetyl chloride, benzoylchloride, trifluoroacetic
anhydride, ethyl formate and phenyl formate. More preferably, the
fifth protective reagent is selected from the group consisting of
di-tert-butyldicarbonat, 1-adamantyl chloroformate (1-Adoc-Cl),
2-adamantyl chloroformate (2-Adoc-Cl), benzyl bromide, acetic
anhydride, acetyl chloride, benzoylchloride, trifluoroacetic
anhydride, ethyl formate and phenyl form ate. Even more preferably,
the fifth protective reagent is selected from the group consisting
of di-tert-butyldicarbonat, 1-adamantyl chloroformate (1-Adoc-Cl),
benzyl bromide, acetic anhydride, trifluoroacetic anhydride and
ethyl formate. Most preferably, the fifth protective reagent is
di-tert-butyldicarbonat.
[0169] Solvents, suitable for contacting the compound obtained from
contacting a compound of formula (9) with a first acid capable of
forming a pharmaceutically acceptable salt with a fifth protective
reagent include organic solvents or mixtures of organic solvents.
Preferably, the solvent is selected from the group consisting of
methanol, ethanol, acetonitrile, acetone, tetrahydrofuran (THF) and
dichloromethane (DCM) or mixtures thereof. More preferably, the
solvent is selected from the group consisting of tetrahydrofuran
(THF) and dichloromethane (DCM) or mixtures thereof. Most
preferably, the solvent is dichloromethane (DCM).
[0170] The molar ratio of the fifth protective group and the
compound of formula (9) when contacting the compound obtained from
contacting the compound of formula (9) with a first acid capable of
forming a pharmaceutically acceptable salt with the fifth
protective reagent is typically at least 0.8, preferably at least
0.9, and most preferably at least 1, and generally at most 1.5,
preferably at most 1.4 and most preferably at most 1.3.
[0171] Generally, the temperature at the step of contacting the
compound obtained from contacting the compound of formula (9) with
a first acid capable of forming a pharmaceutically acceptable salt
with a fifth protective reagent ranges from -10.degree. C. up to
reflux of the solvent or solvent mixture. The temperature at the
step of contacting the compound obtained from contacting the
compound of formula (9) with a first acid capable of forming a
pharmaceutically acceptable salt with a fifth protective reagent is
preferably at least 0.degree. C., more preferably at least
10.degree. C., even more preferably at least 15.degree. C. and most
preferably at least 20.degree. C. The temperature at the step of
contacting the compound of formula (7) with the compound of formula
(7a) to obtain the compound of formula (8) is preferably at most
90.degree. C., more preferably at most 70.degree. C., even more
preferably at most 50.degree. C. and most preferably at most
35.degree. C.
[0172] The invention further pertains to a process for preparing a
compound of formula (12)
##STR00045##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, cycloalkyl, alkoxy, aryloxy, aryl, or alkylaryl and
X is a counter acid, comprising the conversion of a compound of
formula (11)
##STR00046##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, aryl, or arylalkyl, R.sup.42 is H or a protective
group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective
group, with a second acid capable of forming a pharmaceutically
acceptable salt to obtain the compound of formula (12). R.sup.3,
R.sup.7, R.sup.8 and second acid are selected as described
above.
[0173] The invention further pertains to a process for preparing a
compound of formula (12)
##STR00047##
wherein R.sup.7 and R.sup.8 are each independently selected from H,
halogen, alkyl, cycloalkyl, alkoxy, aryloxy, aryl, or arylalkyl and
X is a counter acid, comprising the steps of [0174] a. contacting
dehydroepiandrosteron (DHEA) with a first protective reagent to
form a ketal of compound of formula (1)
[0174] ##STR00048## [0175] wherein R.sup.1 and R.sup.2
independently are protective groups or together form one protective
group; [0176] b. contacting a compound of formula (1) with a second
protective reagent to form a compound of formula (2)
[0176] ##STR00049## [0177] wherein R.sup.1 and R.sup.2 are as
defined for compound of formula (1) and wherein R.sup.3 is a
protective group; [0178] c. contacting a compound of formula (2)
with a borane and a first oxidizing agent to obtain a compound of
formula (3)
[0178] ##STR00050## [0179] wherein R.sup.1 and R.sup.2 are as
defined for compound of formula (1) and R.sup.3 is as defined for
compound of formula (2); [0180] d. contacting a compound of formula
(3) with a second oxidizing agent to obtain a compound of formula
(4)
[0180] ##STR00051## [0181] wherein R.sup.1 and R.sup.2 are as
defined for compound of formula (1) and R.sup.3 is as defined for
compound of formula (2); [0182] e. converting the compound of
formula (4) to a compound of formula (7)
[0182] ##STR00052## [0183] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups, comprising the steps selected from: [0184] i)
contacting the compound of formula (4) with a second base and a
third protective reagent to form a compound of formula (5)
[0184] ##STR00053## [0185] wherein R.sup.4 is a protective group,
and [0186] contacting the compound of formula (5) with a third
oxidizing agent and optionally with a fourth protective reagent to
obtain a compound of formula (6)
[0186] ##STR00054## [0187] wherein R.sup.5 is H or a protective
group; and [0188] contacting the compound of formula (6) with a
fourth oxidizing agent to obtain the compound of formula (7); or
[0189] ii) contacting the compound of formula (4) with a second
base and a third oxidizing agent and optionally with a fourth
protective reagent to obtain a compound of formula (6), wherein the
molar ratio of the third oxidizing agent and the compound of
formula (4) is at most 1.5; and contacting a compound of formula
(6) with a fourth oxidizing agent to obtain the compound of formula
(7); or [0190] iii) contacting the compound of formula (4) with a
second base and a third oxidizing agent and optionally with a
fourth protective reagent to obtain the compound of formula (7),
wherein the molar ratio of the third oxidizing agent and the
compound of formula (4) is at least 1.5; [0191] f. contacting a
compound of formula (7) with a compound of formula (7a)
[0191] NH.sub.2--R.sup.6 (7a) [0192] wherein R.sup.6 is either H or
--OR.sup.6a, wherein R.sup.6a is either H or a protective group, to
obtain a compound of formula (8)
[0192] ##STR00055## [0193] wherein R.sup.1 and R.sup.2 are as
defined for compound of formula (1), R.sup.3 is as defined for
compound of formula (2) and R.sup.6 is as defined above; [0194] g.
contacting a compound of formula (8) with a reducing agent to
obtain a compound of formula (9)
[0194] ##STR00056## [0195] wherein R.sup.1 and R.sup.2 are as
defined for compound of formula (1), R.sup.3 is as defined for
compound of formula (2); [0196] h. contacting a compound of formula
(9) with a first acid which forms a non-toxic salt and optionally a
fifth protective reagent to obtain a compound of formula (10)
[0196] ##STR00057## [0197] wherein R.sup.42 is H or a protective
group, R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective
group, comprising a counter acid X.sup.1 when R.sup.42.dbd.H and
R.sup.43.dbd.H; [0198] i. contacting a compound of formula (10)
with an olefination reagent to obtain a compound of formula
(11)
[0198] ##STR00058## [0199] wherein R.sup.7 and R.sup.8 are each
independently selected from H, halogen, alkyl, aryl, or arylalkyl;
[0200] j. further conversion of a compound of formula (11) with a
second acid which forms a non-toxic salt to obtain a compound of
formula (12). R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7, R.sup.8, R.sup.42, R.sup.43, borane, first oxidizing agen,
second oxidizing agent, third oxidizing agent, fourth oxidizing
agent, first base, second base, third protective reagent, fourth
protective reagent, fifth protective reagent, reducing agent,
olefination reagent, first acid, and second acid are selected as
described above.
[0201] In step a. dehydroepiandrosteron (DHEA) is contacted with a
first protective reagent optionally in the presence of a catalyst
to form a ketal.
[0202] With the term "ketal" of is meant a functional group with
the following general connectivity R.sub.2C(OR').sub.2, where both
R' groups are organic fragments. The central carbon atom has four
bonds to it, and is therefore saturated and has tetrahedral
geometry. The two R'O groups, in the present invention R.sup.1O and
R.sup.2O may be equivalent to each other or not. The two R groups
can be equivalent to each other (a "symmetric ketal") or not (a
"mixed ketal") and may form acyclic or cyclic ketals. Ketalization
is typically acid catalysed with elimination of water. As a
reaction to create a ketal proceeds, water typically must be
removed from the reaction mixture, for example, with a Dean-Stark
apparatus. The formation of ketals reduces the total number of
molecules present and therefore is not favourable with regards to
entropy. A way to improve this may be to use an orthoester, e.g.
trimethyl orthoformate, trimethylorthoacetate or
triethylorthoacetate as a source of alcohol. The reaction
equilibrium may be shifted to the ketal when water is removed from
the reaction system. Examples of such water removal include
azeotropic distillation and trapping water with molecular sieves or
aluminium oxide.
With the term "ketalization" is meant any reaction that yields a
ketal.
[0203] The catalyst to obtain a ketal can be any suitable catalyst
known in the art. Commonly used catalysts for ketalization are
acids. Preferably the catalyst to obtain a ketal in step a. of the
present invention is selected from the group consisting of protic
inorganic acids, inorganic metal salts or complexes, organic protic
acids, acidic ionic liquids or molecular sieves. Preferably, the
catalyst to obtain a ketal in step a. of the present invention is
selected from the group consisting of iodine, HCl, FeCl.sub.3,
TiCl.sub.4, Amberlyst-15, HZSM-5, MCM-41, montmorillonite,
Bi(NO.sub.3).sub.3, bismuth(III) subnitrate (BSN), BiCl.sub.3,
BiBr.sub.3, 2, 3-dichlor-5,6-dicyano-1,4-benzochinon (DDQ),
N-bromosuccinimide (NBS), Sc(NTf.sub.2).sub.3, p-toluenesulfonic
acid, tetrabutylammonium tribromide (TBATB), perchloric acid or
camphor-12 sulfonic acid. More preferably, the catalyst in step a.
of the present invention is selected from the group consisting of
p-toluenesulfonic acid or camphor-12 sulfonic acid. Most
preferably, the catalyst is camphor-12 sulfonic acid.
[0204] In the process of the invention, the first protective
reagent may react to form the protective groups of R.sup.1 and
R.sup.2. The first protective reagent may be one reagent or a
combination of two or more reagents. Preferably, the first
protective reagent is an orthoester or an alcohol. More preferably
the first protective reagent to form a ketal is a monohydric or a
polyhydric alcohol. Even more preferably, the first protective
reagent to form a ketal is selected from the group consisting of
methanol, ethanol, isopropyl alcohol, butyl alcohol, cyclohexanol,
phenol, 1,2-ethanediol or 1,3-propanediol. Even more preferably,
the first protective reagent to from a ketal is 1,3-propanediol or
1,2-ethanediol. Most preferably, the first protective reagent to
from a ketal is 1,2-ethanediol.
[0205] "Polyhydric alcohols" have more than one hydroxyl (--OH)
groups. The simplest example of an alcohol with more than one
hydroxyl group is methanediol or methylene glycol,
HOCH.sub.2OH.
[0206] An alcohol that has one hydroxyl group is called
"monohydric". Monohydric alcohols include methanol, ethanol, and
isopropanol.
[0207] Ketalization of dehydroepiandrosteron (DHEA) to give the
compound of formula (1), step a. of the invention, can be performed
in the absence or presence of a solvent or mixtures of solvents.
Suitable solvents for ketalization are generally known in the art.
Preferred solvents are selected from the group consisting of
benzene, toluene or xylene. The most preferred solvent is
toluene.
[0208] Reaction temperature of the ketalization reaction of
dehydroepiandrosteron (DHEA) to give the compound of formula (1) is
not critical. Generally, the reaction temperature ranges from
0.degree. C. up to the reflux temperature of the solvent or solvent
mixture. Preferably, the reaction temperature is at least 5.degree.
C., more preferably at least 10.degree. C., and most preferably at
least 20.degree. C. Preferably, the reaction temperature is at most
115.degree. C., more preferably the reaction temperature is at most
80.degree. C., even more preferably at most 60.degree. C., even
more preferably at most 45.degree. C., and most preferably at most
35.degree. C.
[0209] The compound of formula (1) may be purified. For example,
the compound of formula (1) may be purified by trituration. With
"trituration" is meant a process used to purify crude chemical
compounds containing soluble impurities. Therefore, a solvent may
be chosen in which the desired product is insoluble and the
undesired by-products are very soluble. The crude material may be
washed with the solvent and filtered, leaving the purified product
in solid form and any impurities in solution.
[0210] A solvent for purification of the compound of formula (1)
resulting from step a. may be selected from non-polar solvents.
More preferably a solvent for purification of the crude compound of
formula (1) is selected from the group consisting of pentane,
cyclopentane, hexane, or cyclohexane. Most preferably, the solvent
for purification of the compound of formula (1) is hexane.
[0211] In step b. of the process of the invention, the compound of
formula (1) is contacted with a second protective reagent,
optionally in the presence of a first base, to form the compound of
formula (2).
[0212] The second protective reagent suitable to obtain the
protective group of R.sup.3 is generally known in the art. Examples
of second protective reagents include the ones described in T. W.
Greene, P. G. M. Wutts "Protective Groups in Organic Synthesis",
John Wiley & Sons, 5.sup.th Ed., 2014, pages 17-374.
[0213] Preferably, the second protective reagent is selected from
the group consisting of alkylsulfate (CH.sub.3SO.sub.4),
alkyliodide (CH.sub.3l), diazoalkane (CH.sub.2N.sub.2),
dialkylhydrogenphosphite ((MeO).sub.2POH), isobutylene
(C.sub.4H.sub.8), allylbromide, trimethylchlorosilane (TMSCl),
trimethylsilyltriflate (TMSOTf), trimethylsilylcyanide (TMSCN),
trimethylsilyldiethylamine, triethylsilylchloride (TESCl),
triisopropylsilylchloride (TIPSCl), t-butyldimethylsilylchloride
(TBDMSCl), t-butyldiphenylsilylchloride (TBDPSCl),
tri-iso-propylsilyloxymethylchloride, chloromethylmethylether
(CMME), bromomethylmethylether, iodomethylmethylether,
dimethoxymethane (CH.sub.2(OMe).sub.2), diethoxyethane
(CH.sub.2(OEt).sub.2 (Phenyldimethylsilyl)methoxymethylchloride
(SMOMCl), ethylvinylether, 2-(chloromethoxy)-2-methylpropane
(t-BuOCH.sub.2Cl), ((tert-butoxymethyl)sulfonyl)benzene
(t-BuOCH.sub.2SO.sub.2Ph), 4-pentenyloxymethylchloride (POMCl),
2-methoxyethoxymethyl chloride (MEMCl), 2,2,
2-trichloroethoxymethoxychloride,
2,2,2-trichloroethoxymethoxybromide,
(4-methoxyphenoxy)methylchloride (p-AOMCl),
p-methoxybenzyloxymethylchloride (PMBMCl), benzyloxymethylchloride
(PhCH.sub.2OCH.sub.2OCl), p-methoxyphenol, p-methoxybenzyl 2,2,
2-trichloroacetimidate, guaiacolmethylchloride
(2-MeOC.sub.6H.sub.4OCH.sub.2Cl), acetic anhydride (Ac.sub.2O),
benzoylchloride (BzCl), benzylbromide, benzylchloride,
iodomethylmethylsulfane (CH.sub.3SHC.sub.21),
chloromethylmethylsulfane (CH.sub.3SHO.sub.2Cl), dimethylsulfide
(CH.sub.3SCH.sub.3), oxalylchloride (0001).sub.2, pivaloyl chloride
(PivCl), 3,4-dihydropyran or tritylchloride. More preferably the
second protective agent is selected from the group consisting of
trimethylchlorosilane (TMSCl), trimethylsilyltriflate (TMSOTf),
trimethylsilylcyanide (TMSCN), trimethylsilyldiethylamine,
triethylsilylchloride (TESCl), triisopropylsilylchloride (TIPSCl),
t-butyldimethylsilylchloride (TBDMSCl),
t-butyldiphenylsilylchloride (TBDPSCl), or
tri-iso-propylsilyloxymethylchloride. Even more preferably the
second protective agent is selected from the group consisting of
trimethylchlorosilane (TMSCl), trimethylsilyltriflate (TMSOTf),
trimethylsilylcyanide (TMSCN), trimethylsilyldiethylamine,
triethylsilylchloride (TESCl), triisopropylsilylchloride (TIPSCl),
t-butyldimethylsilylchloride (TBDMSCl),
t-butyldiphenylsilylchloride (TBDPSCl). Most preferably, the second
protective agent is t-butyldimethylsilylchloride (TBDMSCl).
[0214] In step b. of the process of the invention, a first base may
be present. Preferably, the first base is selected from the group
consisting of imidazole, 4-dimethylaminopyridine (DMAP), pyridine,
2,6-Lutidine, 4-(1-pyrrolidinyl)pyridine (PPY), pyrrole, 1,
4-diazabicyclo[2.2.2]octane (DABCO), trimethylamine and
N,N-diisopropylethylamine (DIPEA) or mixtures thereof. More
preferably, the first base is selected from the group consisting of
imidazole, 4-dimethylaminopyridine (DMAP) and
4-(1-pyrrolidinyl)pyridine (PPY) or mixtures thereof. Even more
preferably, the first base is selected from the group consisting of
imidazole and 4-dimethylamino-pyridine (DMAP). Even more
preferably, the first base is imidazole in the presence
dimethylamino-pyridine (DMAP). Most preferably, the first base is
imidazole.
[0215] Step b. of the present invention may be performed in the
presence of a solvent or a mixture of solvents. Solvents, suitable
in step b. include aprotic organic solvents. Such suitable solvents
include toluene, benzene, xylene, tetrahydrofuran (THF),
dichloromethane (DCM), dimethylformamide (DMF), pyridine or
acetonitrile (MeCN). Preferably, the solvent in step b. of the
present invention is selected from the group consisting of toluene,
benzene, xylene, dichloromethane (DCM), dimethylformamide (DMF),
pyridine or acetonitrile (MeCN). More preferably, the solvent in
step b. of the present invention is selected from the group
consisting of dichlormethane (DCM) or dimethylformamide (DMF). Most
preferably, the solvent is dimethylformamide (DMF).
[0216] One reliable and rapid procedure is the protocol, described
by E. J. Corey (J. Am. Chem. Soc. 1972, 94, 6192) in which the
alcohol is reacted with a silyl chloride and imidazole at high
concentration in DMF.
[0217] In step b. the molar ratio of the second protective reagent
and compound of formula (1) is typically at least 0.8, preferably
at least 0.9, and most preferably at least 1, and generally at most
2, preferably at most 1.8, even more preferably at most 1.6 and
most preferably at most 1.5.
[0218] Generally, the reaction temperature in step b. ranges from
about -78.degree. C. up to the reflux temperature of the solvent.
Preferably the reaction temperature in step b. is above -10.degree.
C. More preferably, the reaction temperature in step b. is above
0.degree. C. Even more preferably the reaction temperature in step
b. is above 10.degree. C. Most preferably the reaction temperature
in step b. is above 20.degree. C. Preferably, the reaction
temperature in step b. is below 115.degree. C. More preferably the
reaction temperature in step b. is below 80.degree. C. Even more
preferably, the reaction temperature in step b. is below 60.degree.
C. Even more preferably, the reaction temperature in step b. is
below 45.degree. C. Most preferably, the reaction temperature in
step b. is below 35.degree. C.
[0219] In step c. the compound of formula (2) is contacted with a
borane and a first oxidizing agent to obtain the compound of
formula (3).
With the term "borane" is meant a member of the group of compounds
with the generic formula of B.sub.xH.sub.y as well as substituted
equivalents thereto which are able to act as hydroborating
reagents.
[0220] Preferably, the borane in step c. of the invention is
selected from the group consisting of diborane (B.sub.2H.sub.6),
monosubstituted boranes or disubstituted boranes. More preferably,
the borane is selected from the group consisting of diborane
(B.sub.2H.sub.6), monochloroborane, monobromoborane,
monoiodoborane, monophenylborane, thexylboran (ThBH.sub.2),
monoisopinocamphenylboran (IpcBH.sub.2), diisopinocampheylboran
(Ipc).sub.2BH, 9-borabicyclo[3.3.1]nonane (9-BBN),
bis-3-methyl-2-butylborane (disiamylborane; Sia.sub.2BH),
dimethoxyborane, dicyclohexylborane (Chx.sub.2BH), diphenylborane,
dimesitylborane (C.sub.6H.sub.2Me.sub.3).sub.2BH or catecholboran.
Most preferably, the borane is diborane (B.sub.2H.sub.6).
[0221] Step c. of the present invention may be performed in the
presence of a solvent or a mixture of solvents. Solvents for the
hydroboration reaction in step c for example include ethers,
toluene, benzene and xylene. Preferably, the solvent in the
hydroboration reaction in step c. of the present invention is
selected from ethers. Preferably, the solvent in the hydroboration
reaction in step c. of the present invention includes dimethyl
ether, diethyl ether, tetrahydrofuran, methyl tert.-butyl ether,
monoglyme, diglyme (as used herein, glyme is defined as a
polyethylene glycol dimethyl ether having the general formula
CH.sub.3(OC.sub.2H.sub.4).sub.nOCH.sub.3 where n is an integer from
1 to 4), and mixtures thereof. Preferably, the solvent is selected
from the group consisting of diethyl ether, tetrahydrofuran or
methyl tert.-butyl ether. More preferably, the solvent is selected
from the group consisting of tetrahydrofuran or methyl tert.-butyl
ether. Most preferably, the solvent is tetrahydrofuran.
[0222] The amount of solvent used is not critical; however,
sufficient amounts of solvent should be used to dissolve the
reactants and prevent excessive heat build-up during the
reaction.
[0223] In carrying out the hydroboration reaction it is preferred
to use a substantially stoichiometric amount of reactants. Use of
an excess of either reactant is not detrimental but causes
unnecessary recycle of unused reactant.
[0224] Reaction temperature of the hydroboration reaction is not
critical. Generally, the reaction temperature in step c. of the
present invention ranges from about -78 C. up to the reflux
temperature of the solvent. Preferably, the reaction temperature in
step c. is at least -10.degree. C., more preferably at least
0.degree. C., even more preferably at least 10.degree. C. and most
preferably at least 20.degree. C. Preferably, the reaction
temperature in step c. is at most 115.degree. C., more preferably
at most 80.degree. C., even more preferably at most 60.degree. C.,
even more preferably at most 45.degree. C. and most preferably at
most 35.degree. C.
[0225] Use of the hydroboration reaction in step c. of the
invention is made to transform a double bond in an unsaturated
cyclic moiety of the compound of formula (2) to an organoborane
which may further be transformed to an alcohol with an oxidizing
agent (i.e. first oxidizing agent).
[0226] The first oxidizing agent is a member of the group of
compounds which is able to oxidize the organoborane moiety of the
compound of formula (2) which may be obtained by hydroboration
reaction and thus may form a C-O group, e.g an alcohol. The first
oxidizing agent of the present invention includes sodium perborate
(NaBO.sub.3) and hydrogen peroxide (H.sub.2O.sub.2). More
preferably, the first oxidizing agent is selected from the group
consisting of sodium perborate (NaBO.sub.3) and hydrogen peroxide
(H.sub.2O.sub.2). Most preferred, as first oxidizing agent of the
invention is sodium perborate (NaBO.sub.3).
[0227] Solvents, suitable for contacting the organoborane moiety of
compound of formula (2) with the first oxidizing agent, are
selected as described for the solvents suitable for the
hydroboration reaction above. Preferably, the solvent for the
hydroboration reaction and contacting the organoborane moiety of
compound of formula (2) with the first oxidizing agent is the
same.
[0228] Generally, the reaction temperature for contacting the
organoborane moiety of compound of formula (2) with the first
oxidizing agent ranges from -20.degree. C. up to reflux of the
solvent or solvent mixture. Preferably, the reaction temperature is
at least -10.degree. C., more preferably at least 0.degree. C.,
even more preferably at least 10.degree. C. and most preferably at
least 20.degree. C. Preferably, the reaction temperature is at most
70.degree. C., more preferably at most 60.degree. C., even more
preferably at most 45.degree. C. and most preferably at most
30.degree. C.
[0229] In step of contacting the organoborane moiety of compound of
formula (2) with the first oxidizing agent, the molar ratio of the
first oxidizing agent and the organoborane moiety of the compound
of formula (2) is typically at least 0.8, preferably at least 0.9,
and most preferably at least 1, and generally at most 2, preferably
at most 1.8, even more preferably at most 1.6 and most preferably
at most 1.5.
[0230] The invention further pertains to a process wherein step a.
and step b. may be performed without intermediate isolation of the
compound of formula (1).
[0231] The invention further pertains to a process wherein step c.
and step d. may be performed without intermediate isolation of the
compound of formula (3).
The invention further pertains to a process wherein step e. may be
performed without intermediate isolation of the compounds of
formula (5) and formula (6). The invention further pertains to a
process wherein step f., step g. and step h. may be performed
without intermediate isolation of the compounds of formula (8) and
formula (9).
[0232] The invention further pertains to a process wherein each or
any of step a. and step b., step c. and step d., step e., and step
f. and step g. and step h. may be performed without isolation of
intermediates formed.
[0233] The invention further pertains to a compound of formula
(13):
##STR00059## [0234] wherein: [0235] R.sup.15 is
--R.sup.20--OR.sup.21; [0236] R.sup.16 is --R.sup.20--OR.sup.21,
--R.sup.24--C(O)OR.sup.25; [0237] R.sup.17 is --CH.sub.2O, or
--CH.sub.2NHR.sup.6; or [0238] R.sup.16 and R.sup.17 together form
--R.sup.26--C(O)--CH.sub.2--, --R.sup.27--COR.sup.28.dbd.CH--,
--R.sup.29--C(O)--CHOH--, [0239]
--R.sup.30C(NR.sup.31)--CHR.sup.32--, --R.sup.33--C(O)--Z--CH
R.sup.34--; [0240] R.sup.18 is --C(O)--, --C(R.sup.36R.sup.37)--,
wherein R.sup.36 is OR.sup.40 and R.sup.37 is OR.sup.41; [0241]
--C(CR.sup.38R.sup.39)--, wherein each R.sup.38 and R.sup.39
independently are C1-C8 alkyl, aryl, or alkylaryl; [0242] R.sup.19
is C1-C4 alkyl; [0243] each R.sup.20, R.sup.24, R.sup.26, R.sup.27,
R.sup.29, R.sup.30, R.sup.33 is independently a direct bond or a
methylene; [0244] each R.sup.21, R.sup.25 is independently hydrogen
or C1-C8 alkyl; [0245] each R.sup.6, R.sup.31, R.sup.32, R.sup.34
is either H or --OR.sup.22, wherein R.sup.22 is either H or a
protective group; R.sup.28 is a protective group; [0246] each
R.sup.40 and R.sup.41 is independently H or a protective group;
[0247] or R.sup.40 and R.sup.41 together form a protective group;
[0248] Z is O or NR.sup.35, wherein R.sup.35 is either H or a
protective group; [0249] or a stereoisomer, enantiomer or tautomer
thereof or a mixture thereof; [0250] or a pharmaceutically
acceptable salt thereof.
[0251] Preferably, R.sup.38 and R.sup.39 are independently C1-C4
alkyl, more preferably methyl. Protective groups R.sup.22,
R.sup.28, R.sup.40, R.sup.41, are selected as described for R.sup.3
above. Protective group R.sup.35 is selected as described for
R.sup.42 above.
[0252] Suitable intermediates in alternative processes to obtain a
compound of formula (12) include
##STR00060## ##STR00061## [0253] wherein R.sup.1, R.sup.2 and
R.sup.3 are protective groups, iPr is isopropyl and Ms is
mesyl.
[0254] Each of these intermediates (compounds of formula 14-22) can
be produced starting from the compound of formula (4) and each of
these intermediates can be transformed to the compound of formula
(9).
[0255] The invention further pertains to a compound of formula
(4)
##STR00062## [0256] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups.
[0257] The invention further pertains to a compound of formula
(5)
##STR00063## [0258] wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4
are protective groups.
[0259] The invention further pertains to a compound of formula
(6)
##STR00064## [0260] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups, and R.sup.5 is H or a protective group.
[0261] The invention further pertains to a compound of formula
(7)
##STR00065## [0262] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups.
[0263] The invention further pertains to a compound of formula
(8)
##STR00066## [0264] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups and R.sup.6 is either H or --OR.sup.22, wherein
R.sup.22 is either H or a protective group.
[0265] The invention further pertains to a compound of formula
(9)
##STR00067## [0266] wherein R.sup.1, R.sup.2 and R.sup.3 are
protective groups.
[0267] The invention further pertains to a compound of formula
(10)
##STR00068## [0268] wherein R.sup.42 is H or a protective group,
R.sup.43 is H or R.sup.3, wherein R.sup.3 is a protective group,
comprising a counter acid X.sup.1 when R.sup.42.dbd.H and
R.sup.43.dbd.H.
[0269] The invention further pertains to any one of compounds 4-9,
14, 16, 17, and 19-22 wherein R.sup.1 and R.sup.2 together form
--CH.sub.2--CH.sub.2--.
[0270] The inventive compounds may exist as single stereoisomers,
racemates and/or mixtures of enantiomers and/or diastereomers. All
such single stereoisomers, racemates and mixtures thereof are
intended to be within the scope of the present invention. In a
preferred aspect, the inventive compounds are used in optically
pure form.
[0271] All intermediates appearing in the process of the invention
may be isolated as solids. In particular compounds of formulae (4),
(5), (6), (7), (8), (9) and (10) may be obtained and isolated as
solids. The atoms, molecules or ions which make up solids may be
arranged in an orderly repeating pattern, or irregularly. Materials
whose constituents are arranged in a regular pattern are known as
crystals. In other materials, there is no long-range order in the
position of the atoms. These solids are known as amorphous
solids.
[0272] The present invention is illustrated by, but not intended to
be limited to, the following examples.
EXAMPLE 1
Preparation of
(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16--
tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-3-ol
(compound of formula (1'), step a.)
##STR00069##
[0274] A reactor was charged with 100 g (1.0 eq.)
dehydroepiandrosteron (DHEA), 800.0 ml (8.0 vol) toluene, 43 g (3.6
eq.) ethylene glycol and 500 mg camphor-12-sulfonic acid. The
reaction mixture was heated to approximately 111.degree. C. and
ethylene glycol was removed. Half of the volume of the reaction
mixture was separated by distillation and allowed to cool to
ambient temperature. To this solution 400 ml (4.0 vol) of hexane
were charged and mixed for 2 hours. The solids were isolated by
filtration, washed four times each with 100 ml (1.0 vol) of hexane
and dried under vacuum at 50.degree. C. to afford 119 g of compound
of formula (1') with 100% yield.
EXAMPLE 2
Preparation of tert-butyl
(((3S,8R,9S,10R,13S,14S)-10,13-dimethyl-1,2,3,4,7,8,9,10,11,12,13,14,15,1-
6-tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-1,3dioxolan]-3-yl)ox-
y)dimethylsilane (compound of formula (2'), step b
##STR00070##
[0276] A reactor was charged with 100.7 g (1.0 eq.) compound of
formula (1'), 24.74 g (1.4 eq.) imidazole, 11.1 g (0.3 eq.)
4-(dimethylamino)-pyridin (4-DMAP) and 504 ml (5.0 vol)
dichloromethane (DCM). The reaction mixture was mixed until a
complete solution was obtained. Subsequently the reaction mixture
was cooled to -10.degree. C. and 57 g (1.25 eq.)
tert-butyldimethylsilyl chloride (TBDMS-Cl) slowly charged while
maintaining the temperature below 15.degree. C. The reaction
contents were then allowed to warm to ambient temperature.
Thereafter, the reaction mixture was diluted with 1,510 ml (15 vol)
methyl-tert-butylether (MTBE) and extracted with 805.6 ml (8.0 vol)
H.sub.2O. After phase separation the organic phase was washed with
a solution of 503.5 ml (5.0 vol) H.sub.2O and 15.91 g (0.25 eq.)
citric acid monohydrate, 201.4 ml (2.0 vol) aqueous solution of
sodium bicarbonate (NaHCO.sub.3 aq. solution), 201.4 ml (2.0 vol)
aqueous solution of sodium chloride (brine), dried over sodium
sulphate, separated by filtration, rinsed with
methyl-tert-butylether (MTBE) and concentrated to dryness under
vaccum at 45.degree. C. to afford 137.8 g of compound of formula
(2') with 100% yield.
EXAMPLE 3
Preparation of
(3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-
hexadecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-6-ol
(compound of formula (3'), step c.)
##STR00071##
[0278] A reactor was charged with a solution of 136.6 g (1.0 eq.)
compound of formula (2') in 683 ml (5.0 vol) tetrahydrofuran (THF)
anhydrous. The solution was cooled to -30.degree. C., slowly
charged with 336 ml (1.1 eq.) borane (BH.sub.3) in tetrahydrofuran
(THF) and mixed at ambient temperature until complete conversion,
monitored by chromatography, was achieved. Thereafter, the reaction
mixture was quenched by drop wise addition of 1,319 ml (9.7 vol)
H.sub.2O and 183.10 g (6.0 eq.) of sodium perborate (NaBO.sub.3)
and mixed at ambient temperature until complete conversion to
compound of formula (3') was achieved, which took approximately 10
hours. Subsequently 2,732 ml (10 vol) methyl-tert-butylether (MTBE)
and 1,366 ml (10 vol) H.sub.2O were charged to the reactor and
mixed. Any remaining excess solids where removed from the present
bi-phasic mixture by filtration and the remaining bi-phasic mixture
was rinsed with 800 ml (5.9 vol) H.sub.2O. Subsequent to phase
separation the aqueous phase was extracted with 1,000 ml (7 vol)
methyl-tert-butylether (MTBE) and the combined organic phases
washed with 273.2 ml (2 vol) brine. Subsequently the separated
organic phase was dried over sodium sulphate. Thereafter the
organic phase was filtered and concentrated in vacuum at 45.degree.
C. The obtained material was dissolved twice with a minimal amount
of ethyl acetate (EtOAc) and concentrated to complete dryness to
afford 136 g of compound of formula (3') with 96% yield.
EXAMPLE 4
Preparation of
(3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethyl-
tetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolan]-6(1H)-o-
ne (compound of formula (4'), step d.)
##STR00072##
[0280] A reactor was charged with a solution of 27.9 g (1.0 eq.)
compound of formula (3') in 83.7 ml (3 vol) ethyl acetate (EtOAc),
167.4 ml (6 vol) dimethyl sulfoxide (DMSO) and 33.6 g (2.0 eq.)
2-iodobenzoic acid (IBX). The reaction mixture was mixed at ambient
temperature until completion of the reaction, which was monitored
by chromatography. Subsequently the reaction mixture was extracted
with 558 ml (20 vol) methyl-tert-butylether (MTBE) and 279 ml (10
vol) H.sub.2O. The contents were separated by filtration and the
obtained cake washed with 50 ml (1.8 vol) methyl-tert-butylether
(MTBE). The liquid phases where collected and the aqueous phase
removed. Thereafter, the organic phase was washed two times each
with 239.5 ml (5 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.)
and one time with 55.8 ml (2 vol) brine. Subsequently, the organic
phase was dried over sodium sulphate, separated by filtration and
concentrated to dryness under vacuum at 60.degree. C. to afford
26.1 g compound of formula (4') with 83% yield.
EXAMPLE 5
Preparation of
tert-butyl(((3S,5S,8R,9S,10R,13S,14S)-10,13-dimethyl-6-((trimethylsilyl)o-
xy)-1,2,3,4,5,8,9,10,11,12,13,14,15,16-tetradecahydrospiro-[cyclopenta[a]p-
henanthrene-17,2'-[1,3]dioxolan]-3-yl)oxy)dimethylsilane (compound
of formula (5'), step e.1))
##STR00073##
[0282] A reactor was charged with 47.6 g (1.0 eq.) of compound of
formula (4') and 238 ml (5 vol) tetrahydrofuran (THF) anhydrous.
The mixture was cooled to -70.degree. C., slowly charged with 77.14
ml (1.5 eq.) lithium diisopropylamide (LDA) and mixed for 3 hours
at -70.degree. C. While keeping the temperature in the range of
-70.degree. C. to -65.degree. C. 15.61 ml (1.2 eq.) trimethylsilyl
chloride (TMS-Cl) were slowly added to the reaction mixture. Upon
completion of the dosing the reaction mixture was allowed to warm
to ambient temperature during a period lasting for approximately 10
hours. Thereafter, the reaction mixture was quenched with 952 ml
(20 vol) aqueous sodium bicarbonate (NaHCO.sub.3 aq.) and extracted
with 952 ml (20 vol) methyl-tert-butylether (MTBE). Subsequently,
the organic phase was washed with 95.2 ml (2 vol) brine and dried
over sodium sulphate. Thereafter the organic phase was filtered,
rinsed with 100 ml (2.1 vol) methyl-tert-butylether (MTBE) and
concentrated to dryness under vacuum at 30-35.degree. C. to afford
55.2 g compound of formula (5') with 100% yield.
EXAMPLE 6
Preparation of
(3S,5S,8R,9S,10R,13S,14S)-3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-10,1-
3-dimethyltetradecahydrospiro[cyclopenta[a]phenanthrene-17,2'-1,3dioxolan]-
-6(1H)-one (compound of formula (6'), step e.1))
##STR00074##
[0284] A reactor was charged with 54.0 g (1.0 eq.) of compound of
formula (5') in 270 ml (5 vol) dichloromethane (DCM) and allowed to
cool to -20.degree. C. While keeping the temperature below
0.degree. C., 26 g (1.15 eq.) meta-Chloroperoxybenzoic acid (mCPBA)
were slowly charged to the reaction mixture and further mixed at a
temperature of 0.degree. C. until completion of the reaction, which
was monitored by chromatography. Thereafter 120 ml (2.2 vol)
aqueous sodium bicarbonate (NaHCO.sub.3 aq.) were charged to the
mixture to adjust the pH to 7-8 at while keeping the temperature at
10.degree. C. 1,080 ml (20 vol) methyl-tert-butylether (MTBE) were
charged to the reaction mixture followed by an extraction which was
performed with 270 ml (5 vol) H.sub.2O. The phases were separated
and the organic phase washed with 270 ml (5 vol) aqueous sodium
bicarbonate (NaHCO.sub.3 aq.), 270 ml (5 vol) brine. Thereafter the
organic phase was dried over sodium sulphate, filtered, rinsed with
100 ml (.about.2 vol) methyl-tert-butylether (MTBE) and
concentrated to dryness under vacuum at 30.degree. C. to afford 55
g of compound of formula (6') with 100% yield.
EXAMPLE 7
Preparation of
(1,2R,5S)-5((tert-butyldimethylsilyl)oxy)-2-((3aS,4R,5S,7aS)-4-formyl-7a--
methyloctahydrospiro[indene-1,2'-[1,3]dioxolan]-5-yl)-2-methylcyclohexane--
1-carboxylic acid (compound of formula (7'), step f.)
##STR00075##
[0286] A reactor was charged with a solution of 62.7 g (1.0 eq.)
compound of formula (6') in 376 ml (6 vol) methanol followed by
charging of 56 g (2 eq.) sodium periodate (NalO.sub.4). The
reaction mixture was mixed at ambient temperature until completion
of the reaction which was monitored by chromatography and lasted
for a period of approximately 10 hours. Thereafter the reaction
mixture was charged with 3,000 ml (.about.48 vol)
methyl-tert-butylether (MTBE) and extracted with 4,000 ml
(.about.64 vol) H.sub.2O. Subsequently the separated organic phase
was washed with 125.4 ml (2 vol) brine, dried over 100 g, filtered,
and concentrated to dryness under vacuum to afford 55.7 g of
compound of formula (7') with 86% yield.
EXAMPLE 8
Preparation of
(3aS,4R,5S,7aS)-4-(aminomethyl)-5-((1R,2S,4S)-4-hydroxy-2-(hydroxymethyl)-
-1-methylcyclohexyl)-7a-methyloctahydro-1H-inden-1-one
4-methylbenzenesulfonate (compound of formula (10'), step g-i.)
##STR00076##
[0288] A solution of 5.0 g (1.0 eq.) compound of formula (7') in
15.0 ml (3 vol) tetrahydrofuran (THF) and 0.61 ml (1.1eq.) 50%
aqueous hydroxylamine (NH.sub.2OH 50% aq.) were mixed over a period
of approximately 10 hours and subsequently charged into 80.8 ml (8
eq.) of a freshly prepared THF solution of 1M aluminium hydride
(AlH.sub.3). The reaction mixture was heated to 60.degree. C. and
mixed for 8 hours, then cooled to ambient temperature and charged
with 16.2 g (5 eq.) of sodium sulfate decahydrate
(Na.sub.2SO.sub.4.10H.sub.2O) followed by mixing lasting 2 hours.
Thereafter the reaction mixture was filtered, the obtained cake
washed three times each with 20 ml (4 vol) tetrahydrofuran (THF)
and three times each with 20 ml (4 vol) methanol. The filtrates
were concentrated and the solvent exchanged with ethanol until
.about.20-30 ml solution remained. Subsequently 2 g (1.05 eq.) of
p-toluenesulfonic acid (p-TSA) monohydrate were charged to the
reactor and mixed for 2 hours at 45.degree. C. The mixture was
cooled to ambient temperature and charged into 300 ml (60 vol)
methyl-tert-butylether (MTBE) at vigorous mixing. The precipitates
were separated by filtration, washed three times each with 20 ml (4
vol) methyl-tert-butylether (MTBE) and dried under vacuum at
ambient temperature to afford 5 g of compound of formula (10') with
100% yield.
Example 9
Preparation of
(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahy-
dro-1H-inden-5-yl)-3-(hydroxymeth)-4-methylcyclohexan-1-ol
(compound of formula (11'), step j.)
##STR00077##
[0290] A reactor was charged with 5.0 g (1.0 eq.) compound of
formula (10') in 50.5 ml (5 eq.) potassium tert.-butoxide (KOt-Bu)
(1M/THF) and the reaction mixture mixed for 20 minutes at ambient
temperature. 14.4 g (4.0 eq.) of Ph.sub.3P.sup.+MeBr.sup.- were
added and the reaction mixture mixed at a temperature of
45-50.degree. C. until complete conversion which took approximately
2 hours, and was monitored by chromatography. Subsequently the
reaction mixture was cooled to 0.degree. C., charged with 20 ml (4
vol) H.sub.2O, evaporated and chased twice each with 20 mil (4 vol)
tetrahydrofuran (THF). The residue was suspended in 100 ml (20 vol)
dichloromethane (DCM), separated by filtration and concentrated.
The crude compound of formula (11') was purified via silica gel
column eluted with 9:1:0.2 DCM/EtOH/7M NH.sub.3:MeOH to afford 1.4
g compound of formula (11'), 95% pure by HPLC. Thereafter, 40 ml of
dichloromethane (DCM) were charged to compound of formula (11') and
mixed at ambient temperature for approximately 10 hours.
Subsequently compound of formula (11') was isolated by filtration,
washed twice each with 10 ml dichloromethane (DCM) and dried under
vacuum to afford 1.2 g of compound of formula (11'), 99.2% pure by
HPLC.
EXAMPLE 10
Preparation of
(1S,3S,4R)-4-((3aS,4R,5S,7aS)-4-(aminomethyl)-7a-methyl-1-methyleneoctahy-
dro-1H-inden-5-yl)-3-(hydroxymethyl)-4-methylcyclohexan-1-ol
acetate (compound of formula (12'), step k.)
##STR00078##
[0292] A reactor was charged with 1.0 g (1 eq.) compound of formula
(11'), 10 ml (10 vol) MeOH and 0.2 g (1.1 eq.) of AcOH,
concentrated in a vacuum and triturated with 20.0 ml (20 vol) CAN.
The solids were separated by filtration and dried under vacuum to
afford 1.18 g compound of formula (12'), 100% yield.
[0293] All examples for steps a. to i. according to the invention
result in a high yield (greater or equal to 86%), step j. according
to the invention results in a yield of at least 40% in combination
with a high purity (>80%) for each of the steps a. to j.
* * * * *